Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T60631 | Target Info | |||
| Target Name | Proto-oncogene c-Ret (RET) | ||||
| Synonyms | RET51; RET receptor tyrosine kinase; RET mutant Y791F; RET mutant V804M; RET mutant V804L; RET mutant S891A; RET mutant M918T; RET mutant G691S; Proto-oncogene tyrosine-protein kinase receptor Ret; PTC; Cadherin family member 12; CDHR16; CDHF12; C-ret | ||||
| Target Type | Successful Target | ||||
| Gene Name | RET | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Adenosine | Ligand Info | |||||
| Structure Description | Crystal structure of RET tyrosine kinase domain bound to adenosine | PDB:4CKJ | ||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | No | [1] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVRALTMGD850 LISFAWQISQ860 GMQYLAEMKL870 VHRDLAARNI 880 LVAEGRKMKI890 SDFGLSRDVY900 EEDSVKRSQG911 RIPVKWMAIE921 SLFDHIYTTQ 931 SDVWSFGVLL941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY 981 RLMLQCWKQE991 PDKRPVFADI1001 SKDLEKMMVK1011 RR
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Intedanib | Ligand Info | |||||
| Structure Description | STRUCTURE OF RET PROTEIN TYROSINE KINASE DOMAIN IN COMPLEX WITH NINTEDANIB | PDB:6NEC | ||||
| Method | X-ray diffraction | Resolution | 1.87 Å | Mutation | No | [2] |
| PDB Sequence |
EDPKWEFPRK
722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE762 NASPSELRDL 772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL812 RGFLRESRKV 822 GPGYLGDERA845 LTMGDLISFA855 WQISQGMQYL865 AEMKLVHRDL875 AARNILVAEG 885 RKMKISDFGL895 SRDVYEEDSY905 VKRSQGRIPV915 KWMAIESLFD925 HIYTTQSDVW 935 SFGVLLWEIV945 TLGGNPYPGI955 PPERLFNLLK965 TGHRMERPDN975 CSEEMYRLML 985 QCWKQEPDKR995 PVFADISKDL1005 EKMMVKR
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LYS728
4.582
THR729
3.807
LEU730
3.700
GLY731
3.636
GLU732
4.250
VAL738
3.805
ALA756
3.471
LYS758
2.805
GLU775
3.429
LEU779
3.361
ILE788
3.474
VAL804
3.535
GLU805
2.801
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| Ligand Name: Pralsetinib | Ligand Info | |||||
| Structure Description | Structure of RET protein tyrosine kinase in complex with pralsetinib | PDB:7JU5 | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [3] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVGERALTM848 GDLISFAWQI858 SQGMQYLAEM868 KLVHRDLAAR 878 NILVAEGRKM888 KISDFGLSRD898 VYSQGRIPVK916 WMAIESLFDH926 IYTTQSDVWS 936 FGVLLWEIVT946 LGGNPYPGIP956 PERLFNLLKT966 GHRMERPDNC976 SEEMYRLMLQ 986 CWKQEPDKRP996 VFADISKDLE1006 KMMVKRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .Q4J or .Q4J2 or .Q4J3 or :3Q4J;style chemicals stick;color identity;select .A:730 or .A:731 or .A:732 or .A:733 or .A:735 or .A:736 or .A:737 or .A:738 or .A:756 or .A:758 or .A:759 or .A:760 or .A:772 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:878 or .A:881 or .A:891; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU730
3.644
GLY731
3.454
GLU732
3.612
GLY733
3.384
PHE735
4.752
GLY736
3.576
LYS737
3.363
VAL738
3.558
ALA756
3.243
LYS758
3.638
MET759
3.219
LEU760
3.790
LEU772
3.366
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Adenine | Ligand Info | |||||
| Structure Description | Structure of WT RET protein tyrosine kinase domain at 1.92A resolution. | PDB:6NJA | ||||
| Method | X-ray diffraction | Resolution | 1.92 Å | Mutation | No | [2] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVERALTMG849 DLISFAWQIS859 QGMQYLAEMK869 LVHRDLAARN 879 ILVAEGRKMK889 ISDFGLSRDV899 EEDSVKRSQG911 RIPVKWMAIE921 SLFDHIYTTQ 931 SDVWSFGVLL941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY 981 RLMLQCWKQE991 PDKRPVFADI1001 SKDLEKMMVK1011 RR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ADE or .ADE2 or .ADE3 or :3ADE;style chemicals stick;color identity;select .A:730 or .A:738 or .A:756 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:810 or .A:881; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: Adenosine monophosphate | Ligand Info | |||||
| Structure Description | Structure of G810A mutant of RET protein tyrosine kinase domain. | PDB:6NE7 | ||||
| Method | X-ray diffraction | Resolution | 1.99 Å | Mutation | Yes | [2] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 ASLRGFLRES819 RKVGERALTM848 GDLISFAWQI858 SQGMQYLAEM868 KLVHRDLAAR 878 NILVAEGRKM888 KISDFGLSRD898 VEEDSVKRSQ910 GRIPVKWMAI920 ESLFDHIYTT 930 QSDVWSFGVL940 LWEIVTLGGN950 PYPGIPPERL960 FNLLKTGHRM970 ERPDNCSEEM 980 YRLMLQCWKQ990 EPDKRPVFAD1000 ISKDLEKMMV1010 KRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .AMP or .AMP2 or .AMP3 or :3AMP;style chemicals stick;color identity;select .A:730 or .A:738 or .A:756 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:881; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Selpercatinib | Ligand Info | |||||
| Structure Description | Structure of RET protein tyrosine kinase in complex with selpercatinib | PDB:7JU6 | ||||
| Method | X-ray diffraction | Resolution | 2.06 Å | Mutation | No | [3] |
| PDB Sequence |
EDPKWEFPRK
722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE762 NASPSELRDL 772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL812 RGFLRESRKV 822 GPGYLGPDER844 ALTMGDLISF854 AWQISQGMQY864 LAEMKLVHRD874 LAARNILVAE 884 GRKMKISDFG894 LSRDVYEEDS904 YVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .Q6G or .Q6G2 or .Q6G3 or :3Q6G;style chemicals stick;color identity;select .A:730 or .A:731 or .A:732 or .A:733 or .A:736 or .A:737 or .A:738 or .A:756 or .A:758 or .A:759 or .A:760 or .A:768 or .A:771 or .A:772 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:881 or .A:892; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU730
3.627
GLY731
3.482
GLU732
3.785
GLY733
3.780
GLY736
3.449
LYS737
3.044
VAL738
3.603
ALA756
3.459
LYS758
4.104
MET759
3.517
LEU760
4.177
GLU768
3.406
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Romiplostim | Ligand Info | |||||
| Structure Description | Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | PDB:2X2M | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [4] |
| PDB Sequence |
GPLSLSVDAF
709 KILDPKWEFP720 RKNLVLGKTL730 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE 762 NASPSELRDL772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL 812 RGFLRESRAL846 TMGDLISFAW856 QISQGMQYLA866 EMKLVHRDLA876 ARNILVAEGR 886 KMKISDFGLS896 RDVYEEDSVK907 RSQGRIPVKW917 MAIESLFDHI927 YTTQSDVWSF 937 GVLLWEIVTL947 GGNPYPGIPP957 ERLFNLLKTG967 HRMERPDNCS977 EEMYRLMLQC 987 WKQEPDKRPV997 FADISKDLEK1007 MMVKRR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .X2M or .X2M2 or .X2M3 or :3X2M;style chemicals stick;color identity;select .A:730 or .A:731 or .A:738 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:881 or .A:891; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: Vandetanib | Ligand Info | |||||
| Structure Description | Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor ZD6474 | PDB:2IVU | ||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | No | [5] |
| PDB Sequence |
GPLSLSVDAF
709 KILDPKWEFP720 RKNLVLGKTL730 GEGEFGKVVK740 ATAFHLKGRA750 GYTTVAVKML 760 KENASPSELR770 DLLSEFNVLK780 QVNHPHVIKL790 YGACSQDGPL800 LLIVEYAKYG 810 SLRGFLRESR820 RALTMGDLIS853 FAWQISQGMQ863 YLAEMKLVHR873 DLAARNILVA 883 EGRKMKISDF893 GLSRDVYEED903 SVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ZD6 or .ZD62 or .ZD63 or :3ZD6;style chemicals stick;color identity;select .A:728 or .A:730 or .A:731 or .A:738 or .A:756 or .A:757 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:881 or .A:891 or .A:892; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LYS728
4.687
LEU730
3.372
GLY731
3.871
VAL738
3.403
ALA756
3.158
VAL757
3.787
LYS758
3.541
GLU775
3.489
LEU779
3.591
ILE788
4.255
LEU802
3.850
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| Ligand Name: L-serine-O-phosphate | Ligand Info | |||||
| Structure Description | Crystal structure of hyper-phosphorylated RET kinase domain with (proximal) juxtamembrane segment | PDB:5FM3 | ||||
| Method | X-ray diffraction | Resolution | 2.95 Å | Mutation | No | [6] |
| PDB Sequence |
DAFKILEDPK
716 WEFPRKNLVL726 GKTLGEGEFG736 KVVKATAFHL746 KGRAGYTTVA756 VKMLKENASP 766 SELRDLLSEF776 NVLKQVNHPH786 VIKLYGACSQ796 DGPLLLIVEY806 AKGSLRGFLR 817 ESALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV882 AEGRKMKISD 892 FGLSRDVYEE902 DSVKRQGRIP914 VKWMAIESLF924 DHITTQSDVW935 SFGVLLWEIV 945 TLGGNPYPGI955 PPERLFNLLK965 TGHRMERPDN975 CSEEMYRLML985 QCWKQEPDKR 995 PVFADISKDL1005 EKMMVK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .SEP or .SEP2 or .SEP3 or :3SEP;style chemicals stick;color identity;select .A:771 or .A:873 or .A:894 or .A:895 or .A:897 or .A:907 or .A:908 or .A:910 or .A:911 or .A:912; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Phosphonotyrosine | Ligand Info | |||||
| Structure Description | Crystal structure of RET tyrosine kinase domain bound to adenosine | PDB:4CKJ | ||||
| Method | X-ray diffraction | Resolution | 1.65 Å | Mutation | No | [1] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIVEYAKY 809 GSLRGFLRES819 RKVRALTMGD850 LISFAWQISQ860 GMQYLAEMKL870 VHRDLAARNI 880 LVAEGRKMKI890 SDFGLSRDVY900 EEDSVKRSQG911 RIPVKWMAIE921 SLFDHIYTTQ 931 SDVWSFGVLL941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY 981 RLMLQCWKQE991 PDKRPVFADI1001 SKDLEKMMVK1011 RR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PTR or .PTR2 or .PTR3 or :3PTR;style chemicals stick;color identity;select .A:770 or .A:873 or .A:897 or .A:899 or .A:903 or .A:904 or .A:906 or .A:907 or .A:926 or .A:927 or .A:928; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: (Z)-5-Amino-3-(4-methoxybenzylidene)indolin-2-one | Ligand Info | |||||
| Structure Description | Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | PDB:2X2L | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [4] |
| PDB Sequence |
GPLSLSVDAF
709 KILPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRK821 VRALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV 882 AEGRKMKISD892 FGLSRDVYEE902 DSVKRSQGRI913 PVKWMAIESL923 FDHIYTTQSD 933 VWSFGVLLWE943 IVTLGGNPYP953 GIPPERLFNL963 LKTGHRMERP973 DNCSEEMYRL 983 MLQCWKQEPD993 KRPVFADISK1003 DLEKMMV
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .X2L or .X2L2 or .X2L3 or :3X2L;style chemicals stick;color identity;select .A:730 or .A:738 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:881 or .A:891 or .A:892; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: 4-[3-Hydroxyanilino]-6,7-Dimethoxyquinazoline | Ligand Info | |||||
| Structure Description | The Discovery of 2-Substituted Phenol Quinazolines as Potent and Selective RET Kinase Inhibitors | PDB:5AMN | ||||
| Method | X-ray diffraction | Resolution | 2.57 Å | Mutation | No | [7] |
| PDB Sequence |
GPLSLSVDAF
709 KIDPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRK821 VERALTMGDL851 ISFAWQISQG861 MQYLAEMKLV871 HRDLAARNIL 881 VAEGRKMKIS891 DFGLSRDVEE902 DSVKRSQGRI913 PVKWMAIESL923 FDHIYTTQSD 933 VWSFGVLLWE943 IVTLGGNPYP953 GIPPERLFNL963 LKTGHRMERP973 DNCSEEMYRL 983 MLQCWKQEPD993 KRPVFADISK1003 DLEKMMV
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .DTQ or .DTQ2 or .DTQ3 or :3DTQ;style chemicals stick;color identity;select .A:730 or .A:731 or .A:738 or .A:756 or .A:757 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:881 or .A:891 or .A:892 or .A:893; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU730
2.716
GLY731
3.518
VAL738
3.570
ALA756
3.185
VAL757
4.612
LYS758
2.751
GLU775
2.296
LEU779
4.206
ILE788
3.519
LEU802
4.486
VAL804
2.824
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| Ligand Name: 1,4-Butanediol | Ligand Info | |||||
| Structure Description | First two Cadherin-like domains from Human RET | PDB:2X2U | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | Yes | [8] |
| PDB Sequence |
LYFSRDAYWE
38 KLYVDQAAGT48 PLLYVHALRD58 APEEVPSFRL68 GQHLYGTYRT78 RLHENNWIRI 88 QEDTGLLYLQ98 RSLDHSSWEK108 LSVRNRGFPL118 LTVYLKVFLS128 ECQWPGCARV 145 YFSFFNTSFP155 ACSSLKPREL165 CFPETRPSFR175 IRENRPPGTF185 HQFRLLPVQF 195 LCPQISVAYR205 LLEGEGLPFR215 SAPDSLEVST225 RWALDREQRE235 KYELVAVCTV 245 HREEVVMVPF258 PVTVYDEDDS268 APEFEN
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .BU1 or .BU12 or .BU13 or :3BU1;style chemicals stick;color identity;select .A:37 or .A:38 or .A:39 or .A:41 or .A:148 or .A:154 or .A:155 or .A:160 or .A:164 or .A:165 or .A:167 or .A:168 or .A:169 or .A:170 or .A:190 or .A:193; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: 1-(4-{(1s,3s)-3-[4-amino-5-(3-amino-4-chlorophenyl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl]cyclobutyl}piperazin-1-yl)ethan-1-one | Ligand Info | |||||
| Structure Description | Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrrolo[2,3-d]pyrimidine inhibitor. | PDB:7RUN | ||||
| Method | X-ray diffraction | Resolution | 3.51 Å | Mutation | No | [9] |
| PDB Sequence |
SVDAFKILED
714 PKWEFPRKNL724 VLGKTLGEGE734 FGKVVKATAF744 HLKGRAGYTT754 VAVKMLKENA 764 SPSELRDLLS774 EFNVLKQVNH784 PHVIKLYGAC794 SQDGPLLLIV804 EYAKGSLRGF 815 LRESRKVRAL846 TMGDLISFAW856 QISQGMQYLA866 EMKLVHRDLA876 ARNILVAEGR 886 KMKISDFGLS896 RDVYEEDSVK907 RQGRIPVKWM918 AIESLFDHIT929 TQSDVWSFGV 939 LLWEIVTLGG949 NPYPGIPPER959 LFNLLKTGHR969 MERPDNCSEE979 MYRLMLQCWK 989 QEPDKRPVFA999 DISKDLEKMM1009 VKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .7QU or .7QU2 or .7QU3 or :37QU;style chemicals stick;color identity;select .A:730 or .A:731 or .A:732 or .A:733 or .A:738 or .A:756 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:810 or .A:811 or .A:878 or .A:881 or .A:891 or .A:892; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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LEU730
3.714
GLY731
4.082
GLU732
4.353
GLY733
3.942
VAL738
3.540
ALA756
3.202
LYS758
3.734
GLU775
3.033
LEU779
3.845
ILE788
4.153
LEU802
4.882
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| Ligand Name: 4-azanyl-7-(1-methylcyclopropyl)-~{N}-(5-methyl-1~{H}-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide | Ligand Info | |||||
| Structure Description | Crystal structure of human Proto-oncogene tyrosine-protein kinase receptor Ret in complex with 4-amino-7-(1-methylcyclopropyl)-N-(5-methyl-1H-pyrazol-3-yl)pyrrolo[2,3-d]pyrimidine-5-carboxamide | PDB:7DUA | ||||
| Method | X-ray diffraction | Resolution | 1.64 Å | Mutation | No | [10] |
| PDB Sequence |
LEDPKWEFPR
721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK761 ENASPSELRD 771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS811 LRGFLRESRK 821 VGPGYLGDER844 ALTMGDLISF854 AWQISQGMQY864 LAEMKLVHRD874 LAARNILVAE 884 GRKMKISDFG894 LSRDVYEEDS904 YVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVK
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .HJ0 or .HJ02 or .HJ03 or :3HJ0;style chemicals stick;color identity;select .A:730 or .A:731 or .A:735 or .A:738 or .A:756 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:811 or .A:878 or .A:881 or .A:891 or .A:892 or .A:893; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU730
3.435
GLY731
3.513
PHE735
3.833
VAL738
3.754
ALA756
3.242
LYS758
3.434
GLU775
2.723
LEU779
3.689
ILE788
4.151
LEU802
3.906
VAL804
3.271
|
|||||
| Ligand Name: 4-(5-((Pyridin-3-ylmethyl)amino)pyrazolo[1,5-a]pyrimidin-3-yl)benzamide | Ligand Info | |||||
| Structure Description | Crystal structure of phosphorylated RET V804M tyrosine kinase domain complexed with PDD00018366 | PDB:6I83 | ||||
| Method | X-ray diffraction | Resolution | 1.88 Å | Mutation | Yes | [11] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIMEYAKY 809 GSLRGFLRES819 RKRALTMGDL851 ISFAWQISQG861 MQYLAEMKLV871 HRDLAARNIL 881 VAEGRKMKIS891 DFGLSRDVYE901 EDSVKRSQGR912 IPVKWMAIES922 LFDHIYTTQS 932 DVWSFGVLLW942 EIVTLGGNPY952 PGIPPERLFN962 LLKTGHRMER972 PDNCSEEMYR 982 LMLQCWKQEP992 DKRPVFADIS1002 KDLEKMMVKR1012 R
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .H72 or .H722 or .H723 or :3H72;style chemicals stick;color identity;select .A:730 or .A:731 or .A:735 or .A:738 or .A:756 or .A:758 or .A:775 or .A:779 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:811 or .A:878 or .A:879 or .A:880 or .A:881 or .A:891 or .A:892 or .A:893; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU730
3.606
GLY731
3.971
PHE735
3.530
VAL738
3.906
ALA756
3.298
LYS758
2.758
GLU775
2.840
LEU779
4.115
ILE788
3.951
MET804
3.310
GLU805
3.309
|
|||||
| Ligand Name: 2',3'-Cyclic AMP | Ligand Info | |||||
| Structure Description | Crystal structure of non-phosphorylated RET tyrosine kinase domain | PDB:2IVS | ||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | No | [5] |
| PDB Sequence |
EDPKWEFPRK
722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE762 NASPSELRDL 772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL812 RGFLRESRKV 822 GPGYLRALTM848 GDLISFAWQI858 SQGMQYLAEM868 KLVHRDLAAR878 NILVAEGRKM 888 KISDFGLSRD898 VYEEDSYVKR908 SQGRIPVKWM918 AIESLFDHIY928 TTQSDVWSFG 938 VLLWEIVTLG948 GNPYPGIPPE958 RLFNLLKTGH968 RMERPDNCSE978 EMYRLMLQCW 988 KQEPDKRPVF998 ADISKDLEKM1008 MVKR
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Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .ACK or .ACK2 or .ACK3 or :3ACK;style chemicals stick;color identity;select .A:730 or .A:731 or .A:732 or .A:733 or .A:738 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:811 or .A:881 or .A:891 or .A:892; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
||||||
| Ligand Name: Ret-IN-3 | Ligand Info | |||||
| Structure Description | Crystal structure of partially phosphorylated RET V804M tyrosine kinase domain complexed with PDD00018412 | PDB:6I82 | ||||
| Method | X-ray diffraction | Resolution | 2.05 Å | Mutation | Yes | [11] |
| PDB Sequence |
GPLSLSVDAF
709 KILEDPKWEF719 PRKNLVLGKT729 LGEGEFGKVV739 KATAFHLKGR749 AGYTTVAVKM 759 LKENASPSEL769 RDLLSEFNVL779 KQVNHPHVIK789 LYGACSQDGP799 LLLIMEYAKY 809 GSLRGFLRES819 ERALTMGDLI852 SFAWQISQGM862 QYLAEMKLVH872 RDLAARNILV 882 AEGRKMKISD892 FGLSRDVYQG911 RIPVKWMAIE921 SLFDHITTQS932 DVWSFGVLLW 942 EIVTLGGNPY952 PGIPPERLFN962 LLKTGHRMER972 PDNCSEEMYR982 LMLQCWKQEP 992 DKRPVFADIS1002 KDLEKMMVKR1012
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .H6W or .H6W2 or .H6W3 or :3H6W;style chemicals stick;color identity;select .A:730 or .A:731 or .A:735 or .A:738 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:811 or .A:878 or .A:879 or .A:881 or .A:891 or .A:892; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: 1-(tert-Butyl)-3-(p-tolyl)-1H-pyrazolo[3,4-d]pyrimidin-4-amine | Ligand Info | |||||
| Structure Description | Crystal structure of phosphorylated RET tyrosine kinase domain complexed with the inhibitor PP1 | PDB:2IVV | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | No | [5] |
| PDB Sequence |
GPLSLSVDAF
709 KIKWEFPRKN723 LVLGKTLGEG733 EFGKVVKATA743 FHLKGRAGYT753 TVAVKMLKEN 763 ASPSELRDLL773 SEFNVLKQVN783 HPHVIKLYGA793 CSQDGPLLLI803 VEYAKYGSLR 813 GFLRESRLTM848 GDLISFAWQI858 SQGMQYLAEM868 SLVHRDLAAR878 NILVAEGRKM 888 KISDFGLSRD898 VYEEDSVKRS909 QGRIPVKWMA919 IESLFDHIYT929 TQSDVWSFGV 939 LLWEIVTLGG949 NPYPGIPPER959 LFNLLKTGHR969 MERPDNCSEE979 MYRLMLQCWK 989 QEPDKRPVFA999 DISKDLEKMM1009 VK
|
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .PP1 or .PP12 or .PP13 or :3PP1;style chemicals stick;color identity;select .A:730 or .A:731 or .A:738 or .A:756 or .A:757 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:810 or .A:811 or .A:878 or .A:881 or .A:891 or .A:892; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU730
3.617
GLY731
3.799
VAL738
3.687
ALA756
3.174
VAL757
4.717
LYS758
3.624
GLU775
3.736
LEU779
4.009
ILE788
4.363
LEU802
4.255
|
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: 2-[4-[[4-[1-[2-(dimethylamino)ethyl]pyrazol-4-yl]-6-[(3-methyl-1~{H}-pyrazol-5-yl)amino]pyrimidin-2-yl]amino]phenyl]-~{N}-(3-fluorophenyl)ethanamide | Ligand Info | |||||
| Structure Description | Structure of RET kinase domain bound to inhibitor JB-48 | PDB:7NZN | ||||
| Method | X-ray diffraction | Resolution | 2.39 Å | Mutation | No | [12] |
| PDB Sequence |
GPLSLSVDAF
709 KIDPKWEFPR721 KNLVLGKTLG731 EGEFGKVVKA741 TAFHLKGRAG751 YTTVAVKMLK 761 ENASPSELRD771 LLSEFNVLKQ781 VNHPHVIKLY791 GACSQDGPLL801 LIVEYAKYGS 811 LRGFLRESRR844 ALTMGDLISF854 AWQISQGMQY864 LAEMKLVHRD874 LAARNILVAE 884 GRKMKISDFG894 LSRDVEEDSV906 KRSQGRIPVK916 WMAIESLFDH926 IYTTQSDVWS 936 FGVLLWEIVT946 LGGNPYPGIP956 PERLFNLLKT966 GHRMERPDNC976 SEEMYRLMLQ 986 CWKQEPDKRP996 VFADISKDLE1006 KMMVKRR
|
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|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .VJH or .VJH2 or .VJH3 or :3VJH;style chemicals stick;color identity;select .A:728 or .A:730 or .A:731 or .A:732 or .A:733 or .A:734 or .A:738 or .A:740 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:818 or .A:874 or .A:878 or .A:879 or .A:881 or .A:891 or .A:892 or .A:895 or .A:914; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LYS728
3.919
LEU730
2.936
GLY731
2.312
GLU732
2.493
GLY733
2.585
GLU734
2.900
VAL738
2.184
LYS740
4.484
ALA756
2.948
LYS758
2.531
ILE788
3.400
VAL804
3.217
GLU805
2.988
TYR806
2.277
|
|||||
| Ligand Name: (3Z)-5-amino-3-[(3,5-dimethyl-1H-pyrrol-2-yl)methylidene]-1,3-dihydro-2H-indol-2-one | Ligand Info | |||||
| Structure Description | Crystal Structure of phosphorylated RET tyrosine kinase domain with inhibitor | PDB:2X2K | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [4] |
| PDB Sequence |
GPLSLSVDAF
709 KIPKWEFPRK722 NLVLGKTLGE732 GEFGKVVKAT742 AFHLKGRAGY752 TTVAVKMLKE 762 NASPSELRDL772 LSEFNVLKQV782 NHPHVIKLYG792 ACSQDGPLLL802 IVEYAKYGSL 812 RGFLRESRKV822 RALTMGDLIS853 FAWQISQGMQ863 YLAEMKLVHR873 DLAARNILVA 883 EGRKMKISDF893 GLSRDVYEED903 SVKRSQGRIP914 VKWMAIESLF924 DHIYTTQSDV 934 WSFGVLLWEI944 VTLGGNPYPG954 IPPERLFNLL964 KTGHRMERPD974 NCSEEMYRLM 984 LQCWKQEPDK994 RPVFADISKD1004 LEKMMVKRR
|
|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .X2K or .X2K2 or .X2K3 or :3X2K;style chemicals stick;color identity;select .A:730 or .A:731 or .A:738 or .A:756 or .A:758 or .A:788 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:881 or .A:891 or .A:892; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
||||||
| Ligand Name: 3-(3,4-dimethoxyphenyl)-5-N-(1-methylpiperidin-4-yl)-6-phenylpyrazolo[1,5-a]pyrimidine-5,7-diamine | Ligand Info | |||||
| Structure Description | Crystal structure of phosphorylated RET tyrosine kinase domain complexed with a pyrazolo[1,5-a]pyrimidine inhibitor | PDB:6VHG | ||||
| Method | X-ray diffraction | Resolution | 2.30 Å | Mutation | No | [13] |
| PDB Sequence |
DAFKILEDPK
716 WEFPRKNLVL726 GKTLGEGEFG736 KVVKATAFHL746 KGRAGYTTVA756 VKMLKENASP 766 SELRDLLSEF776 NVLKQVNHPH786 VIKLYGACSQ796 DGPLLLIVEY806 AKYGSLRGFL 816 RESRRALTMG849 DLISFAWQIS859 QGMQYLAEMK869 LVHRDLAARN879 ILVAEGRKMK 889 ISDFGLSRDV899 YEEDSVKRSQ910 GRIPVKWMAI920 ESLFDHITTQ931 SDVWSFGVLL 941 WEIVTLGGNP951 YPGIPPERLF961 NLLKTGHRME971 RPDNCSEEMY981 RLMLQCWKQE 991 PDKRPVFADI1001 SKDLEKMMVK1011 R
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|||||
|
Click to Show 3D Structure of This Binding Site
set background white;style ions nothing; color 8e8e8e;style chemicals nothing; select .QX1 or .QX12 or .QX13 or :3QX1;style chemicals stick;color identity;select .A:730 or .A:731 or .A:735 or .A:738 or .A:756 or .A:758 or .A:775 or .A:779 or .A:788 or .A:802 or .A:804 or .A:805 or .A:806 or .A:807 or .A:808 or .A:809 or .A:810 or .A:811 or .A:878 or .A:879 or .A:881 or .A:891 or .A:892; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
LEU730
3.416
GLY731
3.602
PHE735
3.342
VAL738
3.603
ALA756
3.398
LYS758
3.595
GLU775
3.431
LEU779
3.915
ILE788
3.691
LEU802
4.845
VAL804
3.480
GLU805
2.796
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Oncogenic RET kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans. Mol Cell. 2014 Mar 6;53(5):738-51. | ||||
| REF 2 | Structural basis of resistance of mutant RET protein-tyrosine kinase to its inhibitors nintedanib and vandetanib. J Biol Chem. 2019 Jul 5;294(27):10428-10437. | ||||
| REF 3 | Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations. Ann Oncol. 2021 Feb;32(2):261-268. | ||||
| REF 4 | Synthesis, structure-activity relationship and crystallographic studies of 3-substituted indolin-2-one RET inhibitors. Bioorg Med Chem. 2010 Feb 15;18(4):1482-96. | ||||
| REF 5 | Structure and chemical inhibition of the RET tyrosine kinase domain. J Biol Chem. 2006 Nov 3;281(44):33577-87. | ||||
| REF 6 | RET Functions as a Dual-Specificity Kinase that Requires Allosteric Inputs from Juxtamembrane Elements. Cell Rep. 2016 Dec 20;17(12):3319-3332. | ||||
| REF 7 | The discovery of 2-substituted phenol quinazolines as potent RET kinase inhibitors with improved KDR selectivity. Eur J Med Chem. 2016 Apr 13;112:20-32. | ||||
| REF 8 | Mammal-restricted elements predispose human RET to folding impairment by HSCR mutations. Nat Struct Mol Biol. 2010 Jun;17(6):726-31. | ||||
| REF 9 | Antitarget Selectivity and Tolerability of Novel Pyrrolo[2,3-d]pyrimidine RET Inhibitors. ACS Med Chem Lett. 2021 Nov 6;12(12):1912-1919. | ||||
| REF 10 | Selective RET inhibitor TAS0953/HM06 | ||||
| REF 11 | Discovery and Optimization of wt-RET/KDR-Selective Inhibitors of RET(V804M) Kinase. ACS Med Chem Lett. 2020 Feb 28;11(4):497-505. | ||||
| REF 12 | Discovery of N-Trisubstituted Pyrimidine Derivatives as Type I RET and RET Gatekeeper Mutant Inhibitors with a Novel Kinase Binding Pose. J Med Chem. 2022 Jan 27;65(2):1536-1551. | ||||
| REF 13 | Efficacy and Tolerability of Pyrazolo[1,5-a]pyrimidine RET Kinase Inhibitors for the Treatment of Lung Adenocarcinoma. ACS Med Chem Lett. 2020 Feb 12;11(4):558-565. | ||||
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