Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T82393 | Target Info | |||
| Target Name | TNF alpha converting enzyme (ADAM17) | ||||
| Synonyms | TNFalpha converting enzyme; TNF-alpha-converting enzyme; TNF-alpha converting enzyme; TNF-alpha convertase; TACE; Snake venom-like protease; Disintegrin and metalloproteinase domain-containing protein 17; CSVP; CD156b antigen; CD156b; ADAM 17; A disintegrin and metalloproteinase domain 17 | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | ADAM17 | ||||
| Biochemical Class | Peptidase | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | N-{(2r)-2-[2-(Hydroxyamino)-2-Oxoethyl]-4-Methylpentanoyl}-3-Methyl-L-Valyl-N-(2-Aminoethyl)-L-Alaninamide | Ligand Info | |||
| Canonical SMILES | CC(C)CC(CC(=O)NO)C(=O)NC(C(=O)NC(C)C(=O)NCCN)C(C)(C)C | ||||
| InChI | 1S/C19H37N5O5/c1-11(2)9-13(10-14(25)24-29)17(27)23-15(19(4,5)6)18(28)22-12(3)16(26)21-8-7-20/h11-13,15,29H,7-10,20H2,1-6H3,(H,21,26)(H,22,28)(H,23,27)(H,24,25)/t12-,13+,15+/m0/s1 | ||||
| InChIKey | LMIQCBIEAHJAMZ-GZBFAFLISA-N | ||||
| PubChem Compound ID | 444587 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 2I47 Crystal structure of catalytic domain of TACE with inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [1] |
| PDB Sequence |
PMKNTCKLLV
229 VADHRFYRYM239 GRGEESTTTN249 YLIELIDRVD259 DIYRNTAWDN269 AGFKGYGIQI 279 EQIRILKSPQ289 EVKPGEKHYN299 MAKSYPNEEK309 DAWDVKMLLE319 QFSFDIAEEA 329 SKVCLAHLFT339 YQDFDMGTLG349 LAYVGSPRAN359 SHGGVCPKAY369 YSPVGKKNIY 379 LNSGLTSTKN389 YGKTILTKEA399 DLVTTHELGH409 NFGAEHDPDG419 LAECAPNEDQ 429 GGKYVMYPIA439 VSGDHENNKM449 FSQCSKQSIY459 KTIESKAQEC469 FQERS |
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|
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||||||
| PDB ID: 3EWJ Crystal structure of catalytic domain of TACE with carboxylate inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | Yes | [2] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPH361 GGVCPKAYYS371 PVGKKNIYLN 381 SGLTSTKNYG391 KTILTKEADL401 VTTHELGHNF411 GAEHDPDGLA421 ECAPNEDQGG 431 KYVMYPIAVS441 GDHENNKMFS451 QCSKQSIYKT461 IESKAQECFQ471 ERSN |
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|
|
MET345
3.214
GLY346
2.932
THR347
3.403
LEU348
2.940
GLY349
3.481
LEU350
4.488
ALA351
4.901
ASN389
3.046
TYR390
2.923
LEU401
4.425
|
|||||
| PDB ID: 3E8R Crystal structure of catalytic domain of TACE with hydroxamate inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [3] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPH361 GGVCPKAYYS371 PVGKKNIYLN 381 SGLTSTKNYG391 KTILTKEADL401 VTTHELGHNF411 GAEHDPDGLA421 ECAPNEDQGG 431 KYVMYPIAGD443 HENNKMFSQC453 SKQSIYKTIE463 SKAQECFQER473 S |
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|
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| PDB ID: 3EDZ Crystal structure of catalytic domain of TACE with hydroxamate inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | Yes | [3] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPR357 ANSHGGVCPK367 AYYSPVGKKN 377 IYLNSGLTST387 KNYGKTILTK397 EADLVTTHEL407 GHNFGAEHDP417 DGLAECAPNE 427 DQGGKYVMYP437 IAVSGDHENN447 KMFSQCSKQS457 IYKTIESKAQ467 ECFQERSN |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:436 or .A:437 or .A:438 or .A:439; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 3KMC Crystal structure of catalytic domain of TACE with tartrate-based inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.80 Å | Mutation | Yes | [4] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPN359 SHGGVCPKAY369 YSPVGKKNIY 379 LNSGLTSTKN389 YGKTILTKEA399 DLVTTHELGH409 NFGAEHDPDG419 LAECAPNEDQ 429 GGKYVMYPIA439 VSGDHENNKM449 FSQCSKQSIY459 KTIESKAQEC469 FQERS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:434 or .A:436 or .A:437 or .A:438 or .A:439 or .A:440; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET345
3.014
GLY346
2.851
THR347
3.213
LEU348
2.682
GLY349
2.928
LEU350
4.237
ALA351
4.931
ASN389
3.378
TYR390
2.854
LEU401
4.477
VAL402
3.861
|
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| PDB ID: 3KME Crystal structure of catalytic domain of TACE with phenyl-pyrrolidinyl-tartrate inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.85 Å | Mutation | Yes | [4] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPH361 GGVCPKAYYS371 PVGKKNIYLN 381 SGLTSTKNYG391 KTILTKEADL401 VTTHELGHNF411 GAEHDPDGLA421 ECAPNEDQGG 431 KYVMYPIAVS441 GDHENNKMFS451 QCSKQSIYKT461 IESKAQECFQ471 ERS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:434 or .A:436 or .A:437 or .A:438 or .A:439; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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MET345
3.158
GLY346
2.688
THR347
3.252
LEU348
2.768
GLY349
3.035
LEU350
4.252
ALA351
4.836
ASN389
3.361
TYR390
3.033
LEU401
4.612
|
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| PDB ID: 3O64 Crystal structure of catalytic domain of TACE with 2-(2-Aminothiazol-4-yl)pyrrolidine-Based Tartrate Diamides | ||||||
| Method | X-ray diffraction | Resolution | 1.88 Å | Mutation | Yes | [5] |
| PDB Sequence |
DPDPMKNTCK
226 LLVVADHRFY236 RYMGRGEEST246 TTNYLIELID256 RVDDIYRNTA266 WDNAGFKGYG 276 IQIEQIRILK286 SPQEVKPGEK296 HYNMAKSYPN306 EEKDAWDVKM316 LLEQFSFDIA 326 EEASKVCLAH336 LFTYQDFDMG346 TLGLAYGGHG362 GVCPKAYYSP372 VGKKNIYLNS 382 GLTSTKNYGK392 TILTKEADLV402 TTHELGHNFG412 AEHDPDGLAE422 CAPNEDQGGK 432 YVMYPIAVSG442 DHENNKMFSQ452 CSKQSIYKTI462 ESKAQECFQE472 RS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:434 or .A:436 or .A:437 or .A:438 or .A:439; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET345
2.970
GLY346
2.689
THR347
3.219
LEU348
2.768
GLY349
3.230
LEU350
4.439
ALA351
4.971
ASN389
3.145
TYR390
2.808
LEU401
4.499
|
|||||
| PDB ID: 3L0T Crystal structure of catalytic domain of TACE with hydantoin inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 1.92 Å | Mutation | Yes | [6] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPS360 HGGVCPKAYY370 SPVGKKNIYL 380 NSGLTSTKNY390 GKTILTKEAD400 LVTTHELGHN410 FGAEHDPDGL420 AECAPNEDQG 430 GKYVMYPIAV440 SGDHENNKMF450 SQCSKQSIYK460 TIESKAQECF470 QERS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:436 or .A:437 or .A:438 or .A:439; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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| PDB ID: 2FV9 Crystal structure of TACE in complex with JMV 390-1 | ||||||
| Method | X-ray diffraction | Resolution | 2.02 Å | Mutation | Yes | [7] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPH361 GGVCPKAYYS371 PVGKKNIYLN 381 SGLTSTKNYG391 KTILTKEADL401 VTTHELGHNF411 GAEHDPDGLA421 ECAPNEDQGG 431 KYVMYPIAVS441 GDHENNKMFS451 QCSKQSIYKT461 IESKAQECFQ471 ERSN |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:434 or .A:436 or .A:437 or .A:438 or .A:439; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET345
2.906
GLY346
2.685
THR347
3.245
LEU348
2.805
GLY349
3.255
LEU350
4.245
ALA351
4.705
ASN389
3.317
TYR390
3.010
LEU401
4.624
|
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| PDB ID: 2DDF Crystal structure of TACE in complex with TAPI-2 | ||||||
| Method | X-ray diffraction | Resolution | 1.70 Å | Mutation | Yes | [7] |
| PDB Sequence |
PDPMKNTCKL
227 LVVADHRFYR237 YMGRGEESTT247 TNYLIELIDR257 VDDIYRNTAW267 DNAGFKGYGI 277 QIEQIRILKS287 PQEVKPGEKH297 YNMAKSYPNE307 EKDAWDVKML317 LEQFSFDIAE 327 EASKVCLAHL337 FTYQDFDMGT347 LGLAYGGSPH361 GGVCPKAYYS371 PVGKKNIYLN 381 SGLTSTKNYG391 KTILTKEADL401 VTTHELGHNF411 GAEHDPDGLA421 ECAPNEDQGG 431 KYVMYPIAVS441 GDHENNKMFS451 QCSKQSIYKT461 IESKAQECFQ471 ERS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:436 or .A:437 or .A:438 or .A:439 or .A:440; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
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MET345
3.333
GLY346
2.988
THR347
3.345
LEU348
2.853
GLY349
3.260
LEU350
4.240
ALA351
4.584
ASN389
3.476
TYR390
2.716
LEU401
4.572
|
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| PDB ID: 1BKC CATALYTIC DOMAIN OF TNF-ALPHA CONVERTING ENZYME (TACE) | ||||||
| Method | X-ray diffraction | Resolution | 2.00 Å | Mutation | Yes | [8] |
| PDB Sequence |
> Chain A
DPMKNTCKLL 228 VVADHRFYRY238 MGRGEESTTT248 NYLIELIDRV258 DDIYRNTAWD268 NAGFKGYGIQ 278 IEQIRILKSP288 QEVKPGEKHY298 NMAKSYPNEE308 KDAWDVKMLL318 EQFSFDIAEE 328 ASKVCLAHLF338 TYQDFDMGTL348 GLAYVGSPRA358 NSHGGVCPKA368 YYSPVGKKNI 378 YLNSGLTSTK388 NYGKTILTKE398 ADLVTTHELG408 HNFGAEHDPD418 GLAECAPNED 428 QGGKYVMYPI438 AVSGDHENNK448 MFSQCSKQSI458 YKTIESKAQE468 CFQER > Chain E DPMKNTCKLL 228 VVADHRFYRY238 MGRGEESTTT248 NYLIELIDRV258 DDIYRNTAWD268 NAGFKGYGIQ 278 IEQIRILKSP288 QEVKPGEKHY298 NMAKSYPNEE308 KDAWDVKMLL318 EQFSFDIAEE 328 ASKVCLAHLF338 TYQDFDMGTL348 GLAYVGSPRA358 NSHGGVCPKA368 YYSPVGKKNI 378 YLNSGLTSTK388 NYGKTILTKE398 ADLVTTHELG408 HNFGAEHDPD418 GKAECAPNED 428 QGGKYVMYPI438 AVSGDHENNK448 MFSQCSKQSI458 YKTIESKAQE468 CFQERS > Chain I MKNTCKLLVV 230 ADHRFYRYMG240 RGEESTTTNY250 LIELIDRVDD260 IYRNTAWDNA270 GFKGYGIQIE 280 QIRILKSPQE290 VKPGEKHYNM300 AKSYPNEEKD310 AWDVKMLLEQ320 FSFDIAEEAS 330 KVCLAHLFTY340 QDFDMGTLGL350 AYVGSPRANS360 HGGVCPKAYY370 SPVGKKNIYL 380 NSGLTSTKNY390 GKTILTKEAD400 LVTTHELGHN410 FGAEHDPDGL420 AECAPNEEQG 430 GKYVMYPIAV440 SGDHENNKMF450 SQCSKQSIYK460 TIESKAQECF470 QERS |
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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 .INN or .INN2 or .INN3 or :3INN;style chemicals stick;color identity;select .A:345 or .A:346 or .A:347 or .A:348 or .A:349 or .A:350 or .A:351 or .A:389 or .A:390 or .A:401 or .A:402 or .A:405 or .A:406 or .A:409 or .A:415 or .A:436 or .A:437 or .A:438 or .A:439 or .E:345 or .E:346 or .E:347 or .E:348 or .E:349 or .E:350 or .E:351 or .E:389 or .E:390 or .E:401 or .E:402 or .E:405 or .E:406 or .E:409 or .E:415 or .E:436 or .E:437 or .E:438 or .E:439 or .I:345 or .I:346 or .I:347 or .I:348 or .I:349 or .I:350 or .I:351 or .I:389 or .I:390 or .I:401 or .I:402 or .I:405 or .I:406 or .I:409 or .I:415 or .I:436 or .I:437 or .I:438 or .I:439; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
MET345[A]
3.402
GLY346[A]
3.098
THR347[A]
3.364
LEU348[A]
3.059
GLY349[A]
3.132
LEU350[A]
3.994
ALA351[A]
4.339
ASN389[A]
3.734
TYR390[A]
2.954
LEU401[A]
4.636
VAL402[A]
3.799
HIS405[A]
3.507
GLU406[A]
2.454
HIS409[A]
3.268
HIS415[A]
3.164
TYR436[A]
3.641
PRO437[A]
3.003
ILE438[A]
3.403
ALA439[A]
2.876
MET345[E]
3.257
GLY346[E]
3.001
THR347[E]
3.193
LEU348[E]
2.745
GLY349[E]
3.019
LEU350[E]
3.690
ALA351[E]
4.205
ASN389[E]
3.482
TYR390[E]
4.548
LEU401[E]
4.692
VAL402[E]
3.778
HIS405[E]
3.584
GLU406[E]
2.518
HIS409[E]
3.585
HIS415[E]
3.163
TYR436[E]
3.726
PRO437[E]
3.047
ILE438[E]
3.340
ALA439[E]
2.840
MET345[I]
3.410
GLY346[I]
2.935
THR347[I]
3.217
LEU348[I]
2.974
GLY349[I]
3.028
LEU350[I]
3.888
ALA351[I]
4.335
ASN389[I]
3.623
TYR390[I]
3.057
LEU401[I]
4.800
VAL402[I]
3.889
HIS405[I]
3.504
GLU406[I]
2.495
HIS409[I]
3.351
HIS415[I]
3.166
TYR436[I]
3.689
PRO437[I]
3.254
ILE438[I]
3.403
ALA439[I]
2.914
|
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Identification of potent and selective TACE inhibitors via the S1 pocket. Bioorg Med Chem Lett. 2007 Jan 1;17(1):34-9. | ||||
| REF 2 | Discovery of novel spirocyclopropyl hydroxamate and carboxylate compounds as TACE inhibitors. Bioorg Med Chem Lett. 2009 Jan 1;19(1):54-7. | ||||
| REF 3 | Discovery of novel hydroxamates as highly potent tumor necrosis factor-alpha converting enzyme inhibitors. Part II: optimization of the S3' pocket. Bioorg Med Chem Lett. 2008 Nov 1;18(21):5809-14. | ||||
| REF 4 | The discovery of novel tartrate-based TNF-alpha converting enzyme (TACE) inhibitors. Bioorg Med Chem Lett. 2010 Feb 1;20(3):1189-93 | ||||
| REF 5 | 2-(2-Aminothiazol-4-yl)pyrrolidine-based tartrate diamides as potent, selective and orally bioavailable TACE inhibitors. Bioorg Med Chem Lett. 2011 May 15;21(10):3172-6. | ||||
| REF 6 | Discovery and SAR of hydantoin TACE inhibitors. Bioorg Med Chem Lett. 2010 Mar 15;20(6):1877-80. | ||||
| REF 7 | Stabilization of the autoproteolysis of TNF-alpha converting enzyme (TACE) results in a novel crystal form suitable for structure-based drug design studies. Protein Eng Des Sel. 2006 Apr;19(4):155-61. | ||||
| REF 8 | Crystal structure of the catalytic domain of human tumor necrosis factor-alpha-converting enzyme. Proc Natl Acad Sci U S A. 1998 Mar 31;95(7):3408-12. | ||||
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