Binding Site Information of Target
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T98896 | Target Info | |||
| Target Name | Aggrecanase (ADAMTS5) | ||||
| Synonyms | Aggrecanase-2; ADMP-2; ADAMTS5; ADAMTS-5; ADAM-TS5; ADAM-TS 5; ADAM-TS 11; A disintegrin and metalloproteinase with thrombospondinmotifs 5 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | ADAMTS5 | ||||
| Biochemical Class | Peptidase | ||||
| UniProt ID | |||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| Ligand Name: Marimastat | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with Marimastat | PDB:3HY7 | ||||
| Method | X-ray diffraction | Resolution | 1.69 Å | Mutation | Yes | [1] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQI
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| Ligand Name: Batimastat | Ligand Info | |||||
| Structure Description | Crystal structure of ADAMTS5 with inhibitor bound | PDB:2RJQ | ||||
| Method | X-ray diffraction | Resolution | 2.60 Å | Mutation | No | [2] |
| PDB Sequence |
SRARQVELLL
273 VADASMARLY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQILGP483 EELPGQTYDA493 TQQCNLTFGP503 EYSVCPGMDV513 CARLWCAVVR 523 QGQMVCLTKK533 LPAVEGTPCG543 KGRICLQGKC553 VD
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| Ligand Name: Aldumastat | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with the Inhibitor GLPG1972 | PDB:6YJM | ||||
| Method | X-ray diffraction | Resolution | 2.25 Å | Mutation | Yes | [3] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGK 326 SLEVSKNAAT336 TLKNFCKWQH346 QHNQLGDDHE356 EHYDAAILFT366 REDLCGHHSC 376 DTLGMADVGT386 ICSPERSCAV396 IEDDGLHAAF406 TVAHEIGHLL416 GLSHDDSKFC 426 EETFGSTEDK436 RLMSSILTSI446 DASKPWSKCT456 SATITEFLDD466 GHGNCLLDLP 476 RKQILVP
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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 .OU5 or .OU52 or .OU53 or :3OU5;style chemicals stick;color identity;select .A:377 or .A:378 or .A:379 or .A:380 or .A:381 or .A:382 or .A:403 or .A:406 or .A:407 or .A:410 or .A:411 or .A:414 or .A:420 or .A:437 or .A:438 or .A:439 or .A:440 or .A:441 or .A:442 or .A:443 or .A:444 or .A:446; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
ASP377
4.469
THR378
3.500
LEU379
2.848
GLY380
2.874
MET381
3.503
ALA382
4.851
HIS403
3.320
PHE406
3.174
THR407
3.677
HIS410
3.389
GLU411
2.700
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| Ligand Name: (2R)-N~4~-hydroxy-2-(3-hydroxybenzyl)-N~1~-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]butanediamide | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with an Amino-2-indanol compound | PDB:3HYG | ||||
| Method | X-ray diffraction | Resolution | 1.40 Å | Mutation | Yes | [1] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQI
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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 .099 or .0992 or .0993 or :3099;style chemicals stick;color identity;select .A:377 or .A:378 or .A:379 or .A:380 or .A:381 or .A:382 or .A:406 or .A:407 or .A:410 or .A:411 or .A:414 or .A:420 or .A:437 or .A:438 or .A:439 or .A:440 or .A:441 or .A:442 or .A:443; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| Ligand Name: (3R)-N~2~-(cyclopropylmethyl)-N~1~-hydroxy-3-(3-hydroxybenzyl)-N~4~-[(1S,2R)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]-L-aspartamide | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with an Amino-2-indanol compound | PDB:3HY9 | ||||
| Method | X-ray diffraction | Resolution | 2.02 Å | Mutation | Yes | [1] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQI
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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 .098 or .0982 or .0983 or :3098;style chemicals stick;color identity;select .A:373 or .A:377 or .A:378 or .A:379 or .A:380 or .A:381 or .A:382 or .A:406 or .A:407 or .A:410 or .A:411 or .A:414 or .A:420 or .A:437 or .A:438 or .A:439 or .A:440 or .A:441 or .A:442 or .A:443; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
HIS373
3.367
ASP377
3.238
THR378
3.227
LEU379
2.558
GLY380
2.915
MET381
4.301
ALA382
4.806
PHE406
4.694
THR407
3.339
HIS410
3.263
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| Ligand Name: (2r)-2-[4-(1,3-Benzodioxol-5-Yl)benzyl]-N~4~-Hydroxy-N~1~-[(1s,2r)-2-Hydroxy-2,3-Dihydro-1h-Inden-1-Yl]butanediamide | Ligand Info | |||||
| Structure Description | Crystal Structure of the Catalytic Domain of ADAMTS-5 in Complex with an Amino-2-indanol compound | PDB:3LJT | ||||
| Method | X-ray diffraction | Resolution | 1.60 Å | Mutation | Yes | [4] |
| PDB Sequence |
ASRARQVELL
272 LVADASMARK282 YGRGLQHYLL292 TLASIANRLY302 SHASIENHIR312 LAVVKVVVLG 322 DKDKSLEVSK332 NAATTLKNFC342 KWQHQHNQLG352 DDHEEHYDAA362 ILFTREDLCG 372 HHSCDTLGMA382 DVGTICSPER392 SCAVIEDDGL402 HAAFTVAHEI412 GHLLGLSHDD 422 SKFCEETFGS432 TEDKRLMSSI442 LTSIDASKPW452 SKCTSATITE462 FLDDGHGNCL 472 LDLPRKQI
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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 .LA3 or .LA32 or .LA33 or :3LA3;style chemicals stick;color identity;select .A:377 or .A:378 or .A:379 or .A:380 or .A:381 or .A:382 or .A:403 or .A:406 or .A:407 or .A:410 or .A:411 or .A:414 or .A:420 or .A:437 or .A:438 or .A:440 or .A:441 or .A:442 or .A:443 or .A:446; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
ASP377
3.488
THR378
3.367
LEU379
2.722
GLY380
2.908
MET381
4.431
ALA382
4.959
HIS403
3.708
PHE406
3.603
THR407
3.288
HIS410
3.407
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| Ligand Name: N-hydroxy-4-({4-[4-(trifluoromethyl)phenoxy]phenyl}sulfonyl)tetrahydro-2H-pyran-4-carboxamide | Ligand Info | |||||
| Structure Description | High Resolution Crystal Structure of the Catalytic Domain of ADAMTS-5 (Aggrecanase-2) | PDB:3B8Z | ||||
| Method | X-ray diffraction | Resolution | 1.40 Å | Mutation | Yes | [5] |
| PDB Sequence |
SRARQVELLL
273 VADASMARKY283 GRGLQHYLLT293 LASIANRLYS303 HASIENHIRL313 AVVKVVVLGD 323 KDKSLEVSKN333 AATTLKNFCK343 WQHQHNQLGD353 DHEEHYDAAI363 LFTREDLCGH 373 HSCDTLGMAD383 VGTICSPERS393 CAVIEDDGLH403 AAFTVAHEIG413 HLLGLSHDDS 423 KFCEETFGST433 EDKRLMSSIL443 TSIDASKPWS453 KCTSATITEF463 LDDGHGNCLL 473 DLPRKQI
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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 .294 or .2942 or .2943 or :3294;style chemicals stick;color identity;select .A:373 or .A:377 or .A:378 or .A:379 or .A:380 or .A:381 or .A:403 or .A:406 or .A:407 or .A:410 or .A:411 or .A:414 or .A:420 or .A:437 or .A:438 or .A:440 or .A:441 or .A:442 or .A:443 or .A:444 or .A:445 or .A:446; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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HIS373
3.718
ASP377
3.908
THR378
3.550
LEU379
2.751
GLY380
3.168
MET381
4.792
HIS403
3.565
PHE406
3.315
THR407
3.826
HIS410
3.027
GLU411
2.534
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structural and inhibition analysis reveals the mechanism of selectivity of a series of aggrecanase inhibitors. J Biol Chem. 2009 Sep 4;284(36):24185-91. | ||||
| REF 2 | Crystal structures of the two major aggrecan degrading enzymes, ADAMTS4 and ADAMTS5. Protein Sci. 2008 Jan;17(1):16-21. | ||||
| REF 3 | Discovery of GLPG1972/S201086, a Potent, Selective, and Orally Bioavailable ADAMTS-5 Inhibitor for the Treatment of Osteoarthritis. J Med Chem. 2021 Mar 25;64(6):2937-2952. | ||||
| REF 4 | Structure analysis reveals the flexibility of the ADAMTS-5 active site. Protein Sci. 2011 Apr;20(4):735-44. | ||||
| REF 5 | High resolution crystal structure of the catalytic domain of ADAMTS-5 (aggrecanase-2). J Biol Chem. 2008 Jan 18;283(3):1501-1507. | ||||
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