Target Binding Site Detail
| Target General Information | Top | ||||
|---|---|---|---|---|---|
| Target ID | T08499 | Target Info | |||
| Target Name | Caterpiller protein 1.1 (NLRP3) | ||||
| Synonyms | PYRIN-containing APAF1-like protein 1; PYPAF1; NALP3; NACHT, LRR and PYD domains-containing protein 3; Cryopyrin; Cold-induced autoinflammatory syndrome 1 protein; CLR1.1; CIAS1; C1orf7; Angiotensin/vasopressin receptor AII/AVP-like | ||||
| Target Type | Clinical trial Target | ||||
| Gene Name | NLRP3 | ||||
| UniProt ID | |||||
| Ligand General Information | Top | ||||
|---|---|---|---|---|---|
| Ligand Name | adenosine diphosphate | Ligand Info | |||
| Canonical SMILES | C1=NC(=C2C(=N1)N(C=N2)C3C(C(C(O3)COP(=O)(O)OP(=O)(O)O)O)O)N | ||||
| InChI | 1S/C10H15N5O10P2/c11-8-5-9(13-2-12-8)15(3-14-5)10-7(17)6(16)4(24-10)1-23-27(21,22)25-26(18,19)20/h2-4,6-7,10,16-17H,1H2,(H,21,22)(H2,11,12,13)(H2,18,19,20)/t4-,6-,7-,10-/m1/s1 | ||||
| InChIKey | XTWYTFMLZFPYCI-KQYNXXCUSA-N | ||||
| PubChem Compound ID | 6022 | ||||
| Drug Binding Sites of Target | Top | |||||
|---|---|---|---|---|---|---|
| PDB ID: 7PZC Cryo-EM structure of the NLRP3 decamer bound to the inhibitor CRID3 | ||||||
| Method | Electron microscopy | Resolution | 3.90 Å | Mutation | No | [1] |
| PDB Sequence |
MASTRCKLAR
12 YLEDLEDVDL22 KKFKMHLEDY32 PPQKGCIPLP42 RGQTEKADHV52 DLATLMIDFN 62 GEEKAWAMAV72 WIFAAINRRD82 LYEKAKRDEP92 KWGSDNARVS102 NPTVICQEDS 112 IEEEWMGLLE122 YLSRISICKM132 KKDYRKKYRK142 YVRSRFQCIE152 ESVSLNKRYT 169 RLRLIKEHRS179 QSPVSPIKME206 LLFDPDDEHS216 EPVHTVVFQG226 AAGIGKTILA 236 RKMMLDWASG246 TLYQDRFDYL256 FYIHCREVSL266 VTQRSLGDLI276 MSCCPDPNPP 286 IHKIVRKPSR296 ILFLMDGFDE306 LQGAFDEHIG316 PLCTDWQKAE326 RGDILLSSLI 336 RKKLLPEASL346 LITTRPVALE356 KLQHLLDHPR366 HVEILGFSEA376 KRKEYFFKYF 386 SDEAQARAAF396 SLIQENEVLF406 TMCFIPLVCW416 IVCTGLKQQM426 ESGKSLAQTS 436 KTTTAVYVFF446 LSSLLQPRGG456 SQEHGLCAHL466 WGLCSLAADG476 IWNQKILFEE 486 SDLRNHGLQK496 ADVSAFLRMN506 LFQKEVDCEK516 FYSFIHMTFQ526 EFFAAMYYLL 536 EEEKEGRTNV546 PGSRLKLPSR556 DVTVLLENYG566 KFEKGYLIFV576 VRFLFGLVNQ 586 ERTSYLEKKL596 SCKISQQIRL606 ELLKWIEVKA616 KAKKLQIQPS626 QLELFYCLYE 636 MQEEDFVQRA646 MDYFPKIEIN656 LSTRMDHMVS666 SFCIENCHRV676 ESLSLGFLHN 686 MPKEEEEEEK696 EGRHLDMVQC706 VLPSSSHAAC716 SHGLVNSHLT726 SSFCRGLFSV 736 LSTSQSLTEL746 DLSDNSLGDP756 GMRVLCETLQ766 HPGCNIRRLW776 LGRCGLSHEC 786 CFDISLVLSS796 NQKLVELDLS806 DNALGDFGIR816 LLCVGLKHLL826 CNLKKLWLVS 836 CCLTSACCQD846 LASVLSTSHS856 LTRLYVGENA866 LGDSGVAILC876 EKAKNPQCNL 886 QKLGLVNSGL896 TSVCCSALSS906 VLSTNQNLTH916 LYLRGNTLGD926 KGIKLLCEGL 936 LHPDCKLQVL946 ELDNCNLTSH956 CCWDLSTLLT966 SSQSLRKLSL976 GNNDLGDLGV 986 MMFCEVLKQQ996 SCLLQNLGLS1006 EMYFNYETKS1016 ALETLQEEKP1026 ELTVVFEPSW 1036
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| PDB ID: 6NPY Cryo-EM structure of NLRP3 bound to NEK7 | ||||||
| Method | Electron microscopy | Resolution | 3.80 Å | Mutation | Yes | [2] |
| PDB Sequence |
IYCAKYRAYV
142 RSRFQCIESL162 NKRYTRLRLI172 KEHRIKMELL206 FDPDDEHSEP216 VHTVVFQGAA 226 GIGKTILARK236 MMLDWASGTL246 YQDRFDYLFY256 IHCREVSLVT266 QRSLGDLIMS 276 CCPDPNPPIH286 KIVRKPSRIL296 FLMDGFDELQ306 GAFDEHIGPL316 CTDWQKAERG 326 DILLSSLIRK336 KLLPEASLLI346 TTRPVALEKL356 QHLLDHPRHV366 EILGFSEAKR 376 KEYFFKYFSD386 EAQARAAFSL396 IQENEVLFTM406 CFIPLVCWIV416 CTGLKQQMES 426 GKSLAQTSKT436 TTAVYVFFLS446 SLLQPRGGLC461 AHLWGLCSLA471 ADGIWNQKIL 481 FEESDLRNHG491 LQKADVSAFL501 RMNLFQKEVD511 CEKFYSFIHM521 TFQEFFAAMY 531 YLLENVPGSR548 LKLPSRENYG564 KFEKGYLIFV574 VRFLFGLVNQ584 ERTAKAKKLQ 620 IQPSQLELFY630 CLYEMQEEDF640 VQRAMDYFPK650 IEIGFLHNMP686 KEEEEEEKEG 696 RHLDMVQCVL706 PSSSHAACSH716 GLVNSHLTSS726 FCRGLFSVLS736 TSQSLTELDL 746 SDNSLGDPGM756 RVLCETLQHP766 GCNIRRLWLG776 RCGLSHECCF786 DISLVLSSNQ 796 KLVELDLSDN806 ALGDFGIRLL816 CVGLKHLLCN826 LKKLWLVSCC836 LTSACCQDLA 846 SVLSTSHSLT856 RLYVGENALG866 DSGVAILCEK876 AKNPQCNLQK886 LGLVNSGLTS 896 VCCSALSSVL906 STNQNLTHLY916 LRGNTLGDKG926 IKLLCEGLLH936 PDCKLQVLEL 946 DNCNLTSHCC956 WDLSTLLTSS966 QSLRKLSLGN976 NDLGDLGVMM986 FCEVLKQQSC 996 LLQNLGLSEM1006 YFNYETKSAL1016 ETLQEEKPEL1026 TVVFEPSW
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| PDB ID: 7VTP Cryo-EM structure of PYD-deleted human NLRP3 hexamer | ||||||
| Method | Electron microscopy | Resolution | 3.23 Å | Mutation | No | [3] |
| PDB Sequence |
DYRKKYRKYV
144 RSRFQCISVS163 LNKRYTRLRL173 IKEHRSPIKM205 ELLFDPDDEH215 SEPVHTVVFQ 225 GAAGIGKTIL235 ARKMMLDWAS245 GTLYQDRFDY255 LFYIHCREVS265 LVTQRSLGDL 275 IMSCCPDPNP285 PIHKIVRKPS295 RILFLMDGFD305 ELQGAFDEHI315 GPLCTDWQKA 325 ERGDILLSSL335 IRKKLLPEAS345 LLITTRPVAL355 EKLQHLLDHP365 RHVEILGFSE 375 AKRKEYFFKY385 FSDEAQARAA395 FSLIQENEVL405 FTMCFIPLVC415 WIVCTGLKQQ 425 MESGKSLAQT435 SKTTTAVYVF445 FLSSLLLCAH465 LWGLCSLAAD475 GIWNQKILFE 485 ESDLRNHGLQ495 KADVSAFLRM505 NLFKFYSFIH522 MTFQEFFAAM532 YYLLPSRDVT 559 VLLENYGKFE569 KGYLIFVVRF579 LFGLVNQERT589 SYLEKKLSCK599 ISQQIRLELL 609 KWIEVKAKAK619 KLQIQPSQLE629 LFYCLYEMQE639 EDFVQRAMDY649 FPKIEINLST 659 RMDHMVSSFC669 IENCHRVESL679 SLGFLHTSSF729 CRGLFSVLST739 SQSLTELDLS 749 DNSLGDPGMR759 VLCETLQHPG769 CNIRRLWLGR779 CGLSHECCFD789 ISLVLSSNQK 799 LVELDLSDNA809 LGDFGIRLLC819 VGLKHLLCNL829 KKLWLVSCCL839 TSACCQDLAS 849 VLSTSHSLTR859 LYVGENALGD869 SGVAILCEKA879 KNPQCNLQKL889 GLVNSGLTSV 899 CCSALSSVLS909 TNQNLTHLYL919 RGNTLGDKGI929 KLLCEGLLHP939 DCKLQVLELD 949 NCNLTSHCCW959 DLSTLLTSSQ969 SLRKLSLGNN979 DLGDLGVMMF989 CEVLKQQSCL 999 LQNLGLSEMY1009 FNYETKSALE1019 TLQEEKPELT1029 VVFEP
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ILE151
4.976
ARG167
3.511
TYR168
3.396
THR169
2.717
ARG170
4.931
LEU171
4.140
ALA227
3.235
ALA228
4.152
GLY229
3.243
ILE230
3.602
GLY231
3.303
|
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| PDB ID: 7ZGU Human NLRP3-deltaPYD hexamer | ||||||
| Method | Electron microscopy | Resolution | 3.40 Å | Mutation | No | [4] |
| PDB Sequence |
KDYRKKYRKY
143 VRSRFQCIES161 VSLNKRYTRL171 RLIKEHFDPD212 DEHSEPVHTV222 VFQGAAGIGK 232 TILARKMMLD242 WASGTLYQDR252 FDYLFYIHCR262 EVSLVTQRSL272 GDLIMSCCPD 282 PNPPIHKIVR292 KPSRILFLMD302 GFDELQGAFD312 EHIGPLCTDW322 QKAERGDILL 332 SSLIRKKLLP342 EASLLITTRP352 VALEKLQHLL362 DHPRHVEILG372 FSEAKRKEYF 382 FKYFSDEAQA392 RAAFSLIQEN402 EVLFTMCFIP412 LVCWIVCTGL422 KQQMESGKSL 432 AQTSKTTTAV442 YVFFLSSLLQ452 PRGGLCAHLW467 GLCSLAADGI477 WNQKILFEES 487 DLRNHGLQKA497 DVSAFLRMNL507 FQKEVDCEKF517 YSFIHMTFQE527 FFAAMYYLLE 537 RLKLPSRDVT559 VLLENYGKFE569 KGYLIFVVRF579 LFGLVNQERT589 SYLEKKLSCK 599 ISQQIRLELL609 KWIEVKAKAK619 KLQIQPSQLE629 LFYCLYEMQE639 EDFVQRAMDY 649 FPKIEINLST659 RMDHMVSSFC669 IENCHRVESL679 SLGFLHHLTS727 SFCRGLFSVL 737 STSQSLTELD747 LSDNSLGDPG757 MRVLCETLQH767 PGCNIRRLWL777 GRCGLSHECC 787 FDISLVLSSN797 QKLVELDLSD807 NALGDFGIRL817 LCVGLKHLLC827 NLKKLWLVSC 837 CLTSACCQDL847 ASVLSTSHSL857 TRLYVGENAL867 GDSGVAILCE877 KAKNPQCNLQ 887 KLGLVNSGLT897 SVCCSALSSV907 LSTNQNLTHL917 YLRGNTLGDK927 GIKLLCEGLL 937 HPDCKLQVLE947 LDNCNLTSHC957 CWDLSTLLTS967 SQSLRKLSLG977 NNDLGDLGVM 987 MFCEVLKQQS997 CLLQNLGLSE1007 MYFNYETKSA1017 LETLQEEKPE1027 LTVVFEPSW |
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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 .ADP or .ADP2 or .ADP3 or :3ADP;style chemicals stick;color identity;select .A:167 or .A:168 or .A:169 or .A:171 or .A:227 or .A:228 or .A:229 or .A:230 or .A:231 or .A:232 or .A:233 or .A:234 or .A:373 or .A:381 or .A:412 or .A:413 or .A:416 or .A:522 or .A:523; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
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| PDB ID: 7ALV Crystal Structure of NLRP3 NACHT domain in complex with a potent inhibitor | ||||||
| Method | X-ray diffraction | Resolution | 2.83 Å | Mutation | No | [5] |
| PDB Sequence |
KDYRKKYRKY
143 VRSRFQCIEL164 NKRYTRLRLI174 KEHSPIKMEL207 LFDPDEPVHT221 VVFQGAAGIG 231 KTILARKMML241 DWASGTLYQD251 RFDYLFYIHC261 REVSLVTQRS271 LGDLIMSCCP 281 DPNPPIHKIV291 RKPSRILFLM301 DGFDELQGAF311 DEHIGPLCTD321 WQKAERGDIL 331 LSSLIRKKLL341 PEASLLITTR351 PVALEKLQHL361 LDHPRHVEIL371 GFSEAKRKEY 381 FFKYFSDEAQ391 ARAAFSLIQE401 NEVLFTMCFI411 PLVCWIVCTG421 LKQQMESGKS 431 LAQTSKTTTA441 VYVFFLSSLL451 CAHLWGLCSL472 AADGIWNQKI482 LFEESDLRNH 492 GLQDVSAFLR504 MNLFQKEVKF517 YSFIHMTFQE527 FFAAMYYLLE537 ESRDVTVLLE 563 NYGKFEKGYL573 IFVVRFLFGL583 VNQERSYLEK594 KLSCKISQQI604 RLELLKWIEV 614 KAKAKKLQIQ624 PSQLELFYCL634 YEMQEEDFVQ644 RAMDYFPKIE654 INLSTRMDHM 664 VSSFCIENCH674 RV
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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 .ADP or .ADP2 or .ADP3 or :3ADP;style chemicals stick;color identity;select .A:167 or .A:168 or .A:169 or .A:170 or .A:171 or .A:226 or .A:227 or .A:228 or .A:229 or .A:230 or .A:231 or .A:232 or .A:233 or .A:234 or .A:373 or .A:381 or .A:412 or .A:413 or .A:416 or .A:522 or .A:523; color #00ffc7; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
ARG167
3.366
TYR168
3.342
THR169
2.765
ARG170
4.973
LEU171
3.556
GLY226
4.909
ALA227
3.728
ALA228
3.969
GLY229
3.040
ILE230
3.761
GLY231
3.114
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| PDB ID: 8ETR CryoEM Structure of NLRP3 NACHT domain in complex with G2394 | ||||||
| Method | Electron microscopy | Resolution | 3.50 Å | Mutation | No | [6] |
| PDB Sequence |
KDYRKKYRKY
143 VRSRFQCILN165 KRYTRLRLIK175 EHIKMELLFD210 PDEPVHTVVF224 QGAAGIGKTI 234 LARKMMLDWA244 SGTLYQDRFD254 YLFYIHCREV264 SLVTQRSLGD274 LIMSCCPDPN 284 PPIHKIVRKP294 SRILFLMDGF304 DELQGAFDEH314 IGPLCTDWQK324 AERGDILLSS 334 LIRKKLLPEA344 SLLITTRPVA354 LEKLQHLLDH364 PRHVEILGFS374 EAKRKEYFFK 384 YFSDEAQARA394 AFSLIQENEV404 LFTMCFIPLV414 CWIVCTGLKQ424 QMESGKSLAQ 434 TSKTTTAVYV444 FFLSSLLCAH465 LWGLCSLAAD475 GIWNQKILFE485 ESDLRNHGLQ 495 KADVSAFLRM505 NLFQKEVKFY518 SFIHMTFQEF528 FAAMYYLLEE538 SRDVTVLLEN 564 YGKFEKGYLI574 FVVRFLFGLV584 NQERSYLEKK595 LSCKISQQIR605 LELLKWIEVK 615 AKAKKLQIQP625 SQLELFYCLY635 EMQEEDFVQR645 AMDYFPKIEI655 NLSTRMDHMV 665 SSFCIENCHR675 V
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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 .ADP or .ADP2 or .ADP3 or :3ADP;style chemicals stick;color identity;select .A:151 or .A:167 or .A:168 or .A:169 or .A:170 or .A:171 or .A:227 or .A:228 or .A:229 or .A:230 or .A:231 or .A:232 or .A:233 or .A:234 or .A:235 or .A:373 or .A:381 or .A:412 or .A:413 or .A:416 or .A:521 or .A:522 or .A:523; color #f3c393; zoom selection;set surface opacity 0.5;set surface Van der Waals surface;set mode all
|
ILE151
4.092
ARG167
3.314
TYR168
2.527
THR169
2.390
ARG170
4.880
LEU171
3.264
ALA227
4.930
ALA228
3.849
GLY229
1.956
ILE230
3.673
GLY231
2.337
LYS232
1.941
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| References | Top | ||||
|---|---|---|---|---|---|
| REF 1 | Structure of the NLRP3 decamer bound to the cytokine release inhibitor CRID3. Nature. 2022 Apr;604(7904):184-189. | ||||
| REF 2 | Structural mechanism for NEK7-licensed activation of NLRP3 inflammasome. Nature. 2019 Jun;570(7761):338-343. | ||||
| REF 3 | Structural basis for the oligomerization-mediated regulation of NLRP3 inflammasome activation. Proc Natl Acad Sci U S A. 2022 Mar 15;119(11):e2121353119. | ||||
| REF 4 | Cryo-EM structure of the NEK7-independent NLRP3 inflammasome | ||||
| REF 5 | Crystal Structure of NLRP3 NACHT Domain With an Inhibitor Defines Mechanism of Inflammasome Inhibition. J Mol Biol. 2021 Dec 3;433(24):167309. | ||||
| REF 6 | Overcoming Preclinical Safety Obstacles to Discover (S)-N-((1,2,3,5,6,7-Hexahydro-s-indacen-4-yl)carbamoyl)-6-(methylamino)-6,7-dihydro-5H-pyrazolo[5,1-b][1,3]oxazine-3-sulfonamide (GDC-2394): A Potent and Selective NLRP3 Inhibitor. J Med Chem. 2022 Nov 10;65(21):14721-14739. | ||||
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