Target Information
| Target General Information | Top | |||||
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| Target ID |
T33901
(Former ID: TTDS00328)
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| Target Name |
Niemann-Pick C1-like protein 1 (NPC1L1)
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| Synonyms |
Niemann-Pick C1 Like 1; NPC1L1
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| Gene Name |
NPC1L1
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| Target Type |
Successful target
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[1] | ||||
| Disease | [+] 1 Target-related Diseases | + | ||||
| 1 | Hyper-lipoproteinaemia [ICD-11: 5C80] | |||||
| Function |
Plays a major role in cholesterol homeostasis. Is critical for the uptake of cholesterol across the plasma membrane of the intestinal enterocyte. Is the direct molecular target of ezetimibe, a drug that inhibits cholesterol absorption. Lack of activity leads to multiple lipid transport defects. The protein may have a function in the transport of multiple lipids and their homeostasis, and may play a critical role in regulating lipid metabolism. Acts as a negative regulator of NPC2 and down- regulates its expression and secretion by inhibiting its maturation and accelerating its degradation.
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| UniProt ID | ||||||
| Sequence |
MAEAGLRGWLLWALLLRLAQSEPYTTIHQPGYCAFYDECGKNPELSGSLMTLSNVSCLSN
TPARKITGDHLILLQKICPRLYTGPNTQACCSAKQLVSLEASLSITKALLTRCPACSDNF VNLHCHNTCSPNQSLFINVTRVAQLGAGQLPAVVAYEAFYQHSFAEQSYDSCSRVRVPAA ATLAVGTMCGVYGSALCNAQRWLNFQGDTGNGLAPLDITFHLLEPGQAVGSGIQPLNEGV ARCNESQGDDVATCSCQDCAASCPAIARPQALDSTFYLGQMPGSLVLIIILCSVFAVVTI LLVGFRVAPARDKSKMVDPKKGTSLSDKLSFSTHTLLGQFFQGWGTWVASWPLTILVLSV IPVVALAAGLVFTELTTDPVELWSAPNSQARSEKAFHDQHFGPFFRTNQVILTAPNRSSY RYDSLLLGPKNFSGILDLDLLLELLELQERLRHLQVWSPEAQRNISLQDICYAPLNPDNT SLYDCCINSLLQYFQNNRTLLLLTANQTLMGQTSQVDWKDHFLYCANAPLTFKDGTALAL SCMADYGAPVFPFLAIGGYKGKDYSEAEALIMTFSLNNYPAGDPRLAQAKLWEEAFLEEM RAFQRRMAGMFQVTFMAERSLEDEINRTTAEDLPIFATSYIVIFLYISLALGSYSSWSRV MVDSKATLGLGGVAVVLGAVMAAMGFFSYLGIRSSLVILQVVPFLVLSVGADNIFIFVLE YQRLPRRPGEPREVHIGRALGRVAPSMLLCSLSEAICFFLGALTPMPAVRTFALTSGLAV ILDFLLQMSAFVALLSLDSKRQEASRLDVCCCVKPQELPPPGQGEGLLLGFFQKAYAPFL LHWITRGVVLLLFLALFGVSLYSMCHISVGLDQELALPKDSYLLDYFLFLNRYFEVGAPV YFVTTLGYNFSSEAGMNAICSSAGCNNFSFTQKIQYATEFPEQSYLAIPASSWVDDFIDW LTPSSCCRLYISGPNKDKFCPSTVNSLNCLKNCMSITMGSVRPSVEQFHKYLPWFLNDRP NIKCPKGGLAAYSTSVNLTSDGQVLDTVAILSPRLEYSGTISAHCNLYLLDSTSRFMAYH KPLKNSQDYTEALRAARELAANITADLRKVPGTDPAFEVFPYTITNVFYEQYLTILPEGL FMLSLCLVPTFAVSCLLLGLDLRSGLLNLLSIVMILVDTVGFMALWGISYNAVSLINLVS AVGMSVEFVSHITRSFAISTKPTWLERAKEATISMGSAVFAGVAMTNLPGILVLGLAKAQ LIQIFFFRLNLLITLLGLLHGLVFLPVILSYVGPDVNPALALEQKRAEEAVAAVMVASCP NHPSRVSTADNIYVNHSFEGSIKGAGAISNFLPNNGRQF Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T50MQN | |||||
| Drugs and Modes of Action | Top | |||||
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| Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
| 1 | Ezetimibe | Drug Info | Approved | Hypercholesterolaemia | [2], [3] | |
| Mode of Action | [+] 1 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | Ezetimibe | Drug Info | [1] | |||
| 2 | Ezetimibe-glucuronide | Drug Info | [4] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Vitamin E | Ligand Info | |||||
| Structure Description | Structure of human NPC1L1 | PDB:7N4U | ||||
| Method | Electron microscopy | Resolution | 3.34 Å | Mutation | No | [5] |
| PDB Sequence |
THTLLGQFFQ
342 GWGTWVASWP352 LTILVLSVIP362 VVALAAGLVF372 TELTTDPVEL382 WSAPNSQARS 392 EKAFHDQHFG402 PFFRTNQVIL412 TAPNRSSYRY422 DSLLLGPKNF432 SGILDLDLLL 442 ELLELQERLR452 HLQVWSPEAQ462 RNISLQDICY472 APLNPDNTSL482 YDCCINSLLQ 492 YFQNNRTLLL502 LTANQTLMGQ512 TSQVDWKDHF522 LYCANAPLTF532 KDGTALALSC 542 MADYGAPVFP552 FLAIGGYKGK562 DYSEAEALIM572 TFSLNNYPAG582 DPRLAQAKLW 592 EEAFLEEMRA602 FQRRMAGMFQ612 VTFMAERSLE622 DEINRTTAED632 LPIFATSYIV 642 IFLYISLALG652 SYSSWSRVMV662 DSKATLGLGG672 VAVVLGAVMA682 AMGFFSYLGI 692 RSSLVILQVV702 PFLVLSVGAD712 NIFIFVLEYQ722 RLPRRPGEPR732 EVHIGRALGR 742 VAPSMLLCSL752 SEAICFFLGA762 LTPMPAVRTF772 ALTSGLAVIL782 DFLLQMSAFV 792 ALLSLDSKRQ802 EASRLDVCCC812 VKPQELPPPG822 QGEGLLLGFF832 QKAYAPFLLH 842 WITRGVVLLL852 FLALFGVSLY862 SMCHISVGLD872 QELALPKDSY882 LLDYFLFLNR 892 YFEVGAPVYF902 VTTLGYNFSS912 EAGMNAICSS922 AGCNNFSFTQ932 KIQYATEFPE 942 QSYLAIPASS952 WVDDFIDWLT962 PSSCCRLYIS972 GPNKDKFCPS982 TVNSLNCLKN 992 CMSITMGSVR1002 PSVEQFHKYL1012 PWFLNDRPNI1022 KCPKGGLAAY1032 STSVNLTSDG 1042 QVLTSRFMAY1052 HKPLKNSQDY1062 TEALRAAREL1072 AANITADLRK1082 VPGTDPAFEV 1092 FPYTITNVFY1102 EQYLTILPEG1112 LFMLSLCLVP1122 TFAVSCLLLG1132 LDLRSGLLNL 1142 LSIVMILVDT1152 VGFMALWGIS1162 YNAVSLINLV1172 SAVGMSVEFV1182 SHITRSFAIS 1192 TKPTWLERAK1202 EATISMGSAV1212 FAGVAMTNLP1222 GILVLGLAKA1232 QLIQIFFFRL 1242 NLLITLLGLL1252 HGLVFLPVIL1262 SYVGPDVNPA1272 LALEQKRAEE1282 AVA |
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PRO379
4.291
LEU382
3.937
TRP383
3.368
PHE404
3.498
THR407
3.407
GLN409
3.695
MET616
4.253
GLU618
4.598
LEU621
3.690
ILE625
3.711
LEU696
4.061
LEU871
4.569
ASP872
4.615
GLN873
3.529
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| Ligand Name: Ezetimibe | Ligand Info | |||||
| Structure Description | Cryo_EM structure of delta N-NPC1L1-EZE | PDB:7DFZ | ||||
| Method | Electron microscopy | Resolution | 3.58 Å | Mutation | No | [6] |
| PDB Sequence |
STHTLLGQFF
341 QGWGTWVASW351 PLTILVLSVI361 PVVALAAGLV371 FTELTTDPVE381 LWSAPNSQAR 391 SEKAFHDQHF401 GPFFRTNQVI411 LTAPNRSSYR421 YDSLLLGPKN431 FSGILDLDLL 441 LELLELQERL451 RHLQVWSPEA461 QRNISLQDIC471 YAPLNPDNTS481 LYDCCINSLL 491 QYFQNNRTLL501 LLTANQTLMG511 QTSQVDWKDH521 FLYCANAPLT531 FKDGTALALS 541 CMADYGAPVF551 PFLAIGGYKG561 KDYSEAEALI571 MTFSLNNYPA581 GDPRLAQAKL 591 WEEAFLEEMR601 AFQRRMAGMF611 QVTFMAERSL621 EDEINRTTAE631 DLPIFATSYI 641 VIFLYISLGL670 GGVAVVLGAV680 MAAMGFFSYL690 GIRSSLVILQ700 VVPFLVLSVG 710 ADNIFIFVLE720 YQRLPRRPGE730 PREVHIGRAL740 GRVAPSMLLC750 SLSEAICFFL 760 GALTPMPAVR770 TFALTSGLAV780 ILDFLLQMSA790 FVALLSLDSK800 LLLGFFQKAY 836 APFLLHWITR846 GVVLLLFLAL856 FGVSLYSMCH866 ISVGLDQELA876 LPKDSYLLDY 886 FLFLNRYFEV896 GAPVYFVTTL906 GYNFSSEAGM916 NAICSSAGCN926 NFSFTQKIQY 936 ATEFPEQSYL946 AIPASSWVDD956 FIDWLTPSSC966 CRLYISGPNK976 DKFCPSTVNS 986 LNCLKNCMSI996 TMGSVRPSVE1006 QFHKYLPWFL1016 NDRPNIKCPK1026 GGLAAYSTSV 1036 NLTSDGQVLA1046 SRFMAYHKPL1056 KNSQDYTEAL1066 RAARELAANI1076 TADLRKVPGT 1086 DPAFEVFPYT1096 ITNVFYEQYL1106 TILPEGLFML1116 SLCLVPTFAV1126 SCLLLGLDLR 1136 SGLLNLLSIV1146 MILVDTVGFM1156 ALWGISYNAV1166 SLINLVSAVG1176 MSVEFVSHIT 1186 RSFAISTKPT1196 WLERAKEATI1206 SMGSAVFAGV1216 AMTNLPGILV1226 LGLAKAQLIQ 1236 IFFFRLNLLI1246 TLLGLLHGLV1256 FLPVILSYVG1266 PDVNPAL
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VAL380
3.229
LEU382
2.887
TRP383
2.772
LEU621
3.169
ILE625
3.053
SER695
4.920
VAL697
3.985
ILE698
2.706
VAL701
4.357
ALA768
3.024
VAL769
4.185
PHE772
3.394
LEU871
3.049
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| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Human Similarity Proteins
Human Pathway Affiliation
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| Protein Name | Pfam ID | Percentage of Identity (%) | E value |
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| Putative uncharacterized protein encoded by LINC01549 (LINC01549) | 46.154 (24/52) | 1.64E-06 | |
| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Fat digestion and absorption | hsa04975 | Affiliated Target |
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| Class: Organismal Systems => Digestive system | Pathway Hierarchy | ||
| Chemical Structure based Activity Landscape of Target | Top |
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| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Profiles in Patients | Top | |||||
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| Target Expression Profile (TEP) | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Fat digestion and absorption | |||||
| WikiPathways | [+] 1 WikiPathways | + | ||||
| 1 | Vitamin A and Carotenoid Metabolism | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Update on patented cholesterol absorption inhibitors. Expert Opin Ther Pat. 2009 Aug;19(8):1083-107. | |||||
| REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 6816). | |||||
| REF 3 | Emerging antidyslipidemic drugs. Expert Opin Emerg Drugs. 2008 Jun;13(2):363-81. | |||||
| REF 4 | Spiroimidazolidinone NPC1L1 inhibitors. 1: Discovery by 3D-similarity-based virtual screening. Bioorg Med Chem Lett. 2009 Jun 1;19(11):2965-8. | |||||
| REF 5 | Structures of dimeric human NPC1L1 provide insight into mechanisms for cholesterol absorption. Sci Adv. 2021 Aug 18;7(34):eabh3997. | |||||
| REF 6 | Structural insights into the mechanism of human NPC1L1-mediated cholesterol uptake. Sci Adv. 2021 Jul 16;7(29):eabg3188. | |||||
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