Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T80276 | Target Info | |||
| Target Name | PI3-kinase alpha (PIK3CA) | ||||
| Synonyms | p110alpha; Serine/threonine protein kinase PIK3CA; PtdIns3kinase subunit p110alpha; PtdIns3kinase subunit alpha; PtdIns-3-kinase subunit p110-alpha; PtdIns-3-kinase subunit alpha; Phosphoinositide3kinase catalytic alpha polypeptide; Phosphoinositide-3-kinase catalytic alpha polypeptide; Phosphatidylinositol 4,5bisphosphate 3kinase catalytic subunit alpha isoform; Phosphatidylinositol 4,5bisphosphate 3kinase 110 kDa catalytic subunit alpha; Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform; Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha; PI3kinase subunit alpha; PI3Kalpha; PI3K-alpha; PI3-kinase subunit alpha | ||||
| Target Type | Successful Target | ||||
| Gene Name | PIK3CA | ||||
| Biochemical Class | Kinase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | Alpelisib | Ligand Info | |||
| Canonical SMILES | CC1=C(SC(=N1)NC(=O)N2CCCC2C(=O)N)C3=CC(=NC=C3)C(C)(C)C(F)(F)F | ||||
| InChI | 1S/C19H22F3N5O2S/c1-10-14(11-6-7-24-13(9-11)18(2,3)19(20,21)22)30-16(25-10)26-17(29)27-8-4-5-12(27)15(23)28/h6-7,9,12H,4-5,8H2,1-3H3,(H2,23,28)(H,25,26,29)/t12-/m0/s1 | ||||
| InChIKey | STUWGJZDJHPWGZ-LBPRGKRZSA-N | ||||
| PubChem Compound ID | 56649450 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7PG6 Crystal Structure of PI3Kalpha in complex with the inhibitor NVP-BYL719 | ||||||
| Method | X-ray diffraction | Resolution | 2.50 Å | Mutation | Yes | [1] |
| PDB Sequence |
PRPSSGELWG
12 IHLMPPRILV22 ECLLPNGMIV32 TLECLREATL42 ITIKHELFKE52 ARKYPLHQLL 62 QDESSYIFVS72 VTQEAEREEF82 FDETRRLCDL92 RLFQPFLKVI102 EPVGNREEKI 112 LNREIGFAIG122 MPVCEFDMVK132 DPEVQDFRRN142 ILNVCKEAVD152 LRDLNSPHSR 162 AMYVYPPNVE172 SSPELPKHIY182 NKLDKGQIIV192 VIWVIVSPNN202 DKQKYTLKIN 212 HDCVPEQVIA222 EAIRKKTRSK232 KLSSEQLKLC242 VLEYQGKYIL252 KVCGCDEYFL 262 EKYPLSQYKY272 IRSCIMLGRM282 PNLMLMAKES292 LYSQLPMDCF302 TMPSYSRRIS 312 TSTKSLWVIN331 SALRIKILCA341 TYVNVNIRDI351 DKIYVRTGIY361 HGGEPLCDNV 371 NTQRVPCSNP381 RWNEWLNYDI391 YIPDLPRAAR401 LCLSICSVKG411 RKGAKEEHCP 421 LAWGNINLFD431 YTDTLVSGKM441 ALNLWPVPHG451 LEDLLNPIGV461 TGSNPNKETP 471 CLELEFDWFS481 SVVKFPDMSV491 IEEHANWSVL523 RENDKEQLKA533 ISTRDPLSEI 543 TEQEKDFLWS553 HRHYCVTIPE563 ILPKLLLSVK573 WNSRDEVAQM583 YCLVKDWPPI 593 KPEQAMELLD603 CNYPDPMVRG613 FAVRCLEKYL623 TDDKLSQYLI633 QLVQVLKYEQ 643 YLDNLLVRFL653 LKKALTNQRI663 GHFFFWHLKS673 EMHNKTVSQR683 FGLLLESYCR 693 ACGMYLKHLN703 RQVEAMEKLI713 NLTDILKQEK723 KDETQKVQMK733 FLVEQMRRPD 743 FMDALQGFLS753 PLNPAHQLGN763 LRLEECRIMS773 SAKRPLWLNW783 ENPDIMSELL 793 FQNNEIIFKN803 GDDLRQDMLT813 LQIIRIMENI823 WQNQGLDLRM833 LPYGCLSIGD 843 CVGLIEVVRN853 SHTIMQIQCK863 GQFNSHTLHQ879 WLKDKNKGEI889 YDAAIDLFTR 899 SCAGYCVATF909 ILGIGDRHNS919 NIMVKDDGQL929 FHIDFGHFLD939 HKKKKFGYKR 949 ERVPFVLTQD959 FLIVISKGAQ969 ECTKTREFER979 FQEMCYKAYL989 AIRQHANLFI 999 NLFSMMLGSG1009 MPELQSFDDI1019 AYIRKTLALD1029 KTEQEALEYF1039 MKQMNDAHHG 1049 GWTTKMDWIF1059 HTIKQH
|
|||||
|
|
MET772
3.497
SER774
4.285
PRO778
3.865
TRP780
3.644
ILE800
3.211
LYS802
3.198
TYR836
3.429
ILE848
3.351
GLU849
3.177
VAL850
3.804
VAL851
2.969
|
|||||
| PDB ID: 4JPS Co-crystal Structures of the Lipid Kinase PI3K alpha with Pan and Isoform Selective Inhibitors | ||||||
| Method | X-ray diffraction | Resolution | 2.20 Å | Mutation | Yes | [2] |
| PDB Sequence |
PPRPSSGELW
11 GIHLMPPRIL21 VECLLPNGMI31 VTLECLREAT41 LITIKHELFK51 EARKYPLHQL 61 LQDESSYIFV71 SVTQEAEREE81 FFDETRRLCD91 LRLFQPFLKV101 IEPVGNREEK 111 ILNREIGFAI121 GMPVCEFDMV131 KDPEVQDFRR141 NILNVCKEAV151 DLRDLNSPHS 161 RAMYVYPPNV171 ESSPELPKHI181 YNKLDKGQII191 VVIWVIVSPN201 NDKQKYTLKI 211 NHDCVPEQVI221 AEAIRKLEYQ247 GKYILKVCGC257 DEYFLEKYPL267 SQYKYIRSCI 277 MLGRMPNLML287 MAKESLYSQL297 PMDCFTMPSY307 SRRISTTKSL327 WVINSALRIK 337 ILCATYVNVN347 IRDIDKIYVR357 TGIYHGGEPL367 CDNVNTQRVP377 CSNPRWNEWL 387 NYDIYIPDLP397 RAARLCLSIC407 SVKGRKGAKE417 EHCPLAWGNI427 NLFDYTDTLV 437 SGKMALNLWP447 VPHGLEDLLN457 PIGVTGSNPN467 KETPCLELEF477 DWFSSVVKFP 487 DMSVIEEHAN497 ENDKEQLKAI534 STRDPLSEIT544 EQEKDFLWSH554 RHYCVTIPEI 564 LPKLLLSVKW574 NSRDEVAQMY584 CLVKDWPPIK594 PEQAMELLDC604 NYPDPMVRGF 614 AVRCLEKYLT624 DDKLSQYLIQ634 LVQVLKYEQY644 LDNLLVRFLL654 KKALTNQRIG 664 HFFFWHLKSE674 MHNKTVSQRF684 GLLLESYCRA694 CGMYLKHLNR704 QVEAMEKLIN 714 LTDILKQEKK724 DETQKVQMKF734 LVEQMRRPDF744 MDALQGFLSP754 LNPAHQLGNL 764 RLEECRIMSS774 AKRPLWLNWE784 NPDIMSELLF794 QNNEIIFKNG804 DDLRQDMLTL 814 QIIRIMENIW824 QNQGLDLRML834 PYGCLSIGDC844 VGLIEVVRNS854 HTIMQIQCKF 872 NSHTLHQWLK882 DKNKGEIYDA892 AIDLFTRSCA902 GYCVATFILG912 IGDRHNSNIM 922 VKDDGQLFHI932 DFGHFLDHKK942 KKFGYKRERV952 PFVLTQDFLI962 VISKGAQECT 972 KTREFERFQE982 MCYKAYLAIR992 QHANLFINLF1002 SMMLGSGMPE1012 LQSFDDIAYI 1022 RKTLALDKTE1032 QEALEYFMKQ1042 MNDAHHGGWT1052 TKMDWIFHT
|
|||||
|
|
ARG770
4.846
MET772
3.811
SER774
4.713
PRO778
3.891
TRP780
3.400
ILE800
3.210
LYS802
3.152
TYR836
3.493
ILE848
3.339
GLU849
3.320
VAL850
3.808
|
|||||
| PDB ID: 7MYO Cryo-EM structure of p110alpha in complex with p85alpha inhibited by BYL-719 | ||||||
| Method | Electron microscopy | Resolution | 2.92 Å | Mutation | No | [3] |
| PDB Sequence |
PRILVECLLP
27 NGMIVTLECL37 REATLITIKH47 ELFKEARKYP57 LHQLLQDESS67 YIFVSVTQEA 77 EREEFFDETR87 RLCDLRLFQP97 FLKVIEPVGN107 REEKILNREI117 GFAIGMPVCE 127 FDMVKDPEVQ137 DFRRNILNVC147 KEAVDLRDLN157 SPHSRAMYVY167 PPNVESSPEL 177 PKHIYNKLDK187 GQIIVVIWVI197 VSPNNDKQKY207 TLKINHDCVP217 EQVIAEAIRK 227 KTRSMLKLCV243 LEYQGKYILK253 VCGCDEYFLE263 KYPLSQYKYI273 RSCIMLGRMP 283 NLMLMAKESL293 YSQLPMDCFT303 MPSYSRRIST313 ATPYMSTKSL327 WVINSALRIK 337 ILCATYVNVN347 IRDIDKIYVR357 TGIYHGGEPL367 CDNVNTQRVP377 CSNPRWNEWL 387 NYDIYIPDLP397 RAARLCLSIC407 SVKGRKGAKE417 EHCPLAWGNI427 NLFDYTDTLV 437 SGKMALNLWP447 VPHGLEDLLN457 PIGVTGSNPN467 KETPCLELEF477 DWFSSVVKFP 487 DMSVIEEHAN497 WSVSRELREN526 DKEQLKAIST536 RDPLSEITEQ546 EKDFLWSHRH 556 YCVTIPEILP566 KLLLSVKWNS576 RDEVAQMYCL586 VKDWPPIKPE596 QAMELLDCNY 606 PDPMVRGFAV616 RCLEKYLTDD626 KLSQYLIQLV636 QVLKYEQYLD646 NLLVRFLLKK 656 ALTNQRIGHF666 FFWHLKSEMH676 NKTVSQRFGL686 LLESYCRACG696 MYLKHLNRQV 706 EAMEKLINLT716 DILKQEKKDE726 TQKVQMKFLV736 EQMRRPDFMD746 ALQGFLSPLN 756 PAHQLGNLRL766 EECRIMSSAK776 RPLWLNWENP786 DIMSELLFQN796 NEIIFKNGDD 806 LRQDMLTLQI816 IRIMENIWQN826 QGLDLRMLPY836 GCLSIGDCVG846 LIEVVRNSHT 856 IMQIQCKGGL866 KFNSHTLHQW880 LKDKNKGEIY890 DAAIDLFTRS900 CAGYCVATFI 910 LGIGDRHNSN920 IMVKDDGQLF930 HIDFGHFLDH940 KKRVPFVLTQ958 DFLIVISKGA 968 QECTKTREFE978 RFQEMCYKAY988 LAIRQHANLF998 INLFSMMLGS1008 GMPELQSFDD 1018 IAYIRKTLAL1028 DKTEQEALEY1038 FMKQMNDAHH1048 GG
|
|||||
|
|
MET772
4.384
SER774
2.593
ALA775
3.679
PRO778
3.684
TRP780
4.012
ILE800
3.741
LYS802
3.778
TYR836
3.323
ILE848
3.488
GLU849
3.988
VAL850
3.411
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | A small-molecule PI3K-alpha activator for cardioprotection and neuroregeneration. Nature. 2023 Jun;618(7963):159-168. | ||||
| REF 2 | Discovery of NVP-BYL719 a potent and selective phosphatidylinositol-3 kinase alpha inhibitor selected for clinical evaluation. Bioorg Med Chem Lett. 2013 Jul 1;23(13):3741-8. | ||||
| REF 3 | Cryo-EM structures of PI3KAlpha reveal conformational changes during inhibition and activation. Proc Natl Acad Sci U S A. 2021 Nov 9;118(45):e2109327118. | ||||
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