Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T12646 | Target Info | |||
| Target Name | Valosin-containing protein p97 (VCP) | ||||
| Synonyms | Valosin-containing protein; Transitional endoplasmic reticulum ATPase; TER ATPase; 15S Mg(2+)-ATPase p97 subunit | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | VCP | ||||
| Biochemical Class | Acid anhydride hydrolase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | CB-5083 | Ligand Info | |||
| Canonical SMILES | CC1=CC2=C(C=CC=C2N1C3=NC4=C(COCC4)C(=N3)NCC5=CC=CC=C5)C(=O)N | ||||
| InChI | 1S/C24H23N5O2/c1-15-12-18-17(22(25)30)8-5-9-21(18)29(15)24-27-20-10-11-31-14-19(20)23(28-24)26-13-16-6-3-2-4-7-16/h2-9,12H,10-11,13-14H2,1H3,(H2,25,30)(H,26,27,28) | ||||
| InChIKey | RDALZZCKQFLGJP-UHFFFAOYSA-N | ||||
| PubChem Compound ID | 73051434 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7RLI Cryo-EM structure of human p97 bound to CB-5083 and ADP. | ||||||
| Method | Electron microscopy | Resolution | 3.10 Å | Mutation | No | [1] |
| PDB Sequence |
NRPNRLIVDE
30 AINEDNSVVS40 LSQPKMDELQ50 LFRGDTVLLK60 GKKRREAVCI70 VLSDDTCSDE 80 KIRMNRVVRN90 NLRVRLGDVI100 SIQPCPDVKY110 GKRIHVLPID120 DTVEGITGNL 130 FEVYLKPYFL140 EAYRPIRKGD150 IFLVRGGMRA160 VEFKVVETDP170 SPYCIVAPDT 180 VIHCEGEPIK190 REDEEESLNE200 VGYDDIGGCR210 KQLAQIKEMV220 ELPLRHPALF 230 KAIGVKPPRG240 ILLYGPPGTG250 KTLIARAVAN260 ETGAFFFLIN270 GPEIMSKLAG 280 ESESNLRKAF290 EEAEKNAPAI300 IFIDELDAIA310 PKREKTHGEV320 ERRIVSQLLT 330 LMDGLKQRAH340 VIVMAATNRP350 NSIDPALRRF360 GRFDREVDIG370 IPDATGRLEI 380 LQIHTKNMKL390 ADDVDLEQVA400 NETHGHVGAD410 LAALCSEAAL420 QAIRKKMDLI 430 DLEDETIDAE440 VMNSLAVTMD450 DFRWALSQSN460 PSALRETVVE470 VPQVTWEDIG 480 GLEDVKRELQ490 ELVQYPVEHP500 DKFLKFGMTP510 SKGVLFYGPP520 GCGKTLLAKA 530 IANECQANFI540 SIKGPELLTM550 WFGESEANVR560 EIFDKARQAA570 PCVLFFDELD 580 SIAKARGGNI590 GDGGGAADRV600 INQILTEMDG610 MSTKKNVFII620 GATNRPDIID 630 PAILRPGRLD640 QLIYIPLPDE650 KSRVAILKAN660 LRKSPVAKDV670 DLEFLAKMTN 680 GFSGADLTEI690 CQRACKLAIR700 ESIESEIVPE730 IRRDHFEEAM740 RFARRSVSDN 750 DIRKYEMFAQ760 TLQQSRGFGS770 FRFPS
|
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|
|
VAL474
3.438
ASP478
3.163
ILE479
3.526
GLY480
4.699
LEU482
4.513
GLY521
3.297
CYS522
3.480
GLY523
3.531
LEU526
3.021
LEU527
4.691
|
|||||
| PDB ID: 7RLJ Cryo-EM structure of human p97 bound to CB-5083 and ATPgS. | ||||||
| Method | Electron microscopy | Resolution | 3.80 Å | Mutation | No | [1] |
| PDB Sequence |
NRPNRLIVDE
30 AINEDNSVVS40 LSQPKMDELQ50 LFRGDTVLLK60 GKKRREAVCI70 VLSDDTCSDE 80 KIRMNRVVRN90 NLRVRLGDVI100 SIQPCPDVKY110 GKRIHVLPID120 DTVEGITGNL 130 FEVYLKPYFL140 EAYRPIRKGD150 IFLVRGGMRA160 VEFKVVETDP170 SPYCIVAPDT 180 VIHCEGEPIK190 REDEEESLNE200 VGYDDIGGCR210 KQLAQIKEMV220 ELPLRHPALF 230 KAIGVKPPRG240 ILLYGPPGTG250 KTLIARAVAN260 ETGAFFFLIN270 GPEIMSKLAG 280 ESESNLRKAF290 EEAEKNAPAI300 IFIDELDAIA310 PKREKTHGEV320 ERRIVSQLLT 330 LMDGLKQRAH340 VIVMAATNRP350 NSIDPALRRF360 GRFDREVDIG370 IPDATGRLEI 380 LQIHTKNMKL390 ADDVDLEQVA400 NETHGHVGAD410 LAALCSEAAL420 QAIRKKMDLI 430 DLEDETIDAE440 VMNSLAVTMD450 DFRWALSQSN460 PSALRETVVE470 VPQVTWEDIG 480 GLEDVKRELQ490 ELVQYPVEHP500 DKFLKFGMTP510 SKGVLFYGPP520 GCGKTLLAKA 530 IANECQANFI540 SIKGPELLTM550 WFGESEANVR560 EIFDKARQAA570 PCVLFFDELD 580 SIAKARGGNI590 GDGGGAADRV600 INQILTEMDG610 MSTKKNVFII620 GATNRPDIID 630 PAILRPGRLD640 QLIYIPLPDE650 KSRVAILKAN660 LRKSPVAKDV670 DLEFLAKMTN 680 GFSGADLTEI690 CQRACKLAIR700 ESIESEIVPE730 IRRDHFEEAM740 RFARRSVSDN 750 DIRKYEMFAQ760 TLQQSRGF
|
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|
|
||||||
| PDB ID: 6MCK p97 D1D2 with CB5083 bound | ||||||
| Method | X-ray diffraction | Resolution | 3.77 Å | Mutation | No | [2] |
| PDB Sequence |
RKQLAQIKEM
219 VELPLRHPAL229 FKAIGVKPPR239 GILLYGPPGT249 GKTLIARAVA259 NETGAFFFLI 269 NGPEIMSKLA279 GESESNLRKA289 FEEAEKNAPA299 IIFIDELDAI309 APKREKTHGE 319 VERRIVSQLL329 TLMDGLKQRA339 HVIVMAATNR349 PNSIDPALRR359 FGRFDREVDI 369 GIPDATGRLE379 ILQIHTKNMK389 LADDVDLEQV399 ANETHGHVGA409 DLAALCSEAA 419 LQAIRVTMDD451 FRWALSQSNP461 SALRETVVEV471 PQVTWEDIGG481 LEDVKRELQE 491 LVQYPVEHPD501 KFLKFGMTPS511 KGVLFYGPPG521 CGKTLLAKAI531 ANECQANFIS 541 IKGPELLTMW551 FGESEANVRE561 IFDKARQAAP571 CVLFFDELDS581 IAKARAADRV 600 INQILTEMDG610 MSTKKNVFII620 GATNRPDIID630 PAILRPGRLD640 QLIYIPLPDE 650 KSRVAILKAN660 LRKSPVAKDV670 DLEFLAKMTN680 GFSGADLTEI690 CQRACKLAIR 700 ESIESEIRRE710 RERQTEIRRD734 HFEEAMRFAR744 RSVSDNDIRK754 YEMFAQTLQ |
|||||
|
|
VAL474
3.951
ASP478
3.007
ILE479
3.267
GLY480
4.296
LEU482
3.588
GLY521
4.218
CYS522
3.720
GLY523
3.517
LEU526
2.996
LEU527
4.238
PRO648
4.904
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | AAA+ ATPase p97/VCP mutants and inhibitor binding disrupt inter-domain coupling and subsequent allosteric activation. J Biol Chem. 2021 Oct;297(4):101187. | ||||
| REF 2 | Structural Basis of p97 Inhibition by the Site-Selective Anticancer Compound CB-5083. Mol Pharmacol. 2019 Mar;95(3):286-293. | ||||
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