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- PDB-6pzp: Crystal structure of caspase-1 in complex with VX-765 -

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Basic information

Entry
Database: PDB / ID: 6pzp
TitleCrystal structure of caspase-1 in complex with VX-765
Components(Caspase-1) x 2
KeywordsIMMUNE SYSTEM / protease / complex / inhibitor
Function / homology
Function and homology information


caspase-1 / protease inhibitor complex / AIM2 inflammasome complex assembly / The AIM2 inflammasome / The IPAF inflammasome / AIM2 inflammasome complex / IPAF inflammasome complex / icosanoid biosynthetic process / NLRP1 inflammasome complex / cytokine precursor processing ...caspase-1 / protease inhibitor complex / AIM2 inflammasome complex assembly / The AIM2 inflammasome / The IPAF inflammasome / AIM2 inflammasome complex / IPAF inflammasome complex / icosanoid biosynthetic process / NLRP1 inflammasome complex / cytokine precursor processing / canonical inflammasome complex / positive regulation of interleukin-18 production / NLRP3 inflammasome complex / CARD domain binding / caspase binding / positive regulation of tumor necrosis factor-mediated signaling pathway / Interleukin-1 processing / osmosensory signaling pathway / Interleukin-37 signaling / pattern recognition receptor signaling pathway / : / signaling receptor ligand precursor processing / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptotic inflammatory response / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / The NLRP3 inflammasome / protein autoprocessing / protein maturation / Pyroptosis / Purinergic signaling in leishmaniasis infection / positive regulation of interleukin-1 beta production / NOD1/2 Signaling Pathway / kinase binding / cellular response to type II interferon / positive regulation of inflammatory response / cellular response to mechanical stimulus / SARS-CoV-1 activates/modulates innate immune responses / regulation of inflammatory response / cellular response to lipopolysaccharide / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / microtubule / defense response to virus / endopeptidase activity / defense response to bacterium / cysteine-type endopeptidase activity / apoptotic process / nucleolus / signal transduction / protein-containing complex / proteolysis / identical protein binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
Caspase recruitment domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. ...Caspase recruitment domain / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Peptidase family C14A, His active site / Caspase family histidine active site. / Peptidase C14, caspase non-catalytic subunit p10 / Peptidase family C14A, cysteine active site / Caspase family cysteine active site. / Caspase family p10 domain profile. / Peptidase C14A, caspase catalytic domain / Caspase, interleukin-1 beta converting enzyme (ICE) homologues / Peptidase C14, p20 domain / Caspase family p20 domain profile. / : / Caspase domain / Caspase-like domain superfamily / Death-like domain superfamily
Similarity search - Domain/homology
Chem-P7S / Caspase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.94 Å
AuthorsYang, J. / Liu, Z. / Xiao, T.S.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Human Genome Research Institute (NIH/NHGRI)GM127609 United States
CitationJournal: To Be Published
Title: Crystal structure of caspase-1 in complex with VX-765
Authors: Yang, J. / Liu, Z. / Xiao, T.S.
History
DepositionAug 1, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 5, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Caspase-1
B: Caspase-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,6103
Polymers30,1292
Non-polymers4811
Water2,810156
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5770 Å2
ΔGint-29 kcal/mol
Surface area13300 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.605, 63.605, 162.107
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11B-503-

HOH

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Components

#1: Protein Caspase-1 / CASP-1 / Interleukin-1 beta convertase / IL-1BC / Interleukin-1 beta-converting enzyme / IL-1 beta- ...CASP-1 / Interleukin-1 beta convertase / IL-1BC / Interleukin-1 beta-converting enzyme / IL-1 beta-converting enzyme / p45


Mass: 19869.838 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP1, IL1BC, IL1BCE / Production host: Escherichia coli (E. coli) / References: UniProt: P29466, caspase-1
#2: Protein Caspase-1 / CASP-1 / Interleukin-1 beta convertase / IL-1BC / Interleukin-1 beta-converting enzyme / IL-1 beta- ...CASP-1 / Interleukin-1 beta convertase / IL-1BC / Interleukin-1 beta-converting enzyme / IL-1 beta-converting enzyme / p45


Mass: 10258.755 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP1, IL1BC, IL1BCE / Production host: Escherichia coli (E. coli) / References: UniProt: P29466, caspase-1
#3: Chemical ChemComp-P7S / N-(4-amino-3-chlorobenzene-1-carbonyl)-3-methyl-L-valyl-N-[(2S)-1-carboxy-3-oxopropan-2-yl]-L-prolinamide


Mass: 480.942 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H29ClN4O6 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 156 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.76 Å3/Da / Density % sol: 55.42 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2 M sodium formate, 20% w/v PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.9201 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Aug 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9201 Å / Relative weight: 1
ReflectionResolution: 1.935→28.89 Å / Num. obs: 25637 / % possible obs: 99.4 % / Redundancy: 14.2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.082 / Net I/av σ(I): 19.7 / Net I/σ(I): 19.7
Reflection shellResolution: 1.94→1.99 Å / Redundancy: 13 % / Rmerge(I) obs: 1.197 / Mean I/σ(I) obs: 1.7 / Num. unique obs: 1727 / CC1/2: 0.812 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX1.12_2829refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6BZ9

6bz9


Resolution: 1.94→28.885 Å / SU ML: 0.2 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 20.97
RfactorNum. reflection% reflection
Rfree0.2079 1998 7.82 %
Rwork0.1671 --
obs0.1702 25536 99.39 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 134.65 Å2 / Biso mean: 47.2287 Å2 / Biso min: 23.9 Å2
Refinement stepCycle: final / Resolution: 1.94→28.885 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2075 0 33 156 2264
Biso mean--52.47 48.7 -
Num. residues----262
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072158
X-RAY DIFFRACTIONf_angle_d0.8422910
X-RAY DIFFRACTIONf_chiral_restr0.055320
X-RAY DIFFRACTIONf_plane_restr0.005373
X-RAY DIFFRACTIONf_dihedral_angle_d4.7891658
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.94-1.98380.29411300.2743152992
1.9838-2.03740.29041390.22081652100
2.0374-2.09730.23941400.20751640100
2.0973-2.1650.25521390.18381644100
2.165-2.24230.21621420.17981665100
2.2423-2.33210.2271400.17581658100
2.3321-2.43820.20841430.17881684100
2.4382-2.56660.19961420.17791667100
2.5666-2.72730.21551430.18041692100
2.7273-2.93770.22641430.17331665100
2.9377-3.2330.2131450.17431713100
3.233-3.70.1761450.15481717100
3.7-4.65850.18531480.13441740100
4.6585-28.8850.21351590.16941872100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.0504-0.15180.65170.1754-0.24540.4631-0.29770.6791-0.8357-0.05190.02510.25230.75840.3421-0.00630.5654-0.02210.1660.2487-0.11140.4945-20.5092-49.872-9.5846
21.43710.7732-0.60280.6228-0.34481.9360.337-0.2716-0.7176-0.13340.34021.2753-0.5786-1.30070.17790.3842-0.3825-0.00660.803-0.18091.229-36.5815-39.778-10.1734
30.0165-0.0027-0.14410.1893-0.09550.05040.30220.64010.2078-0.3998-0.16110.09310.064-0.521300.3623-0.0479-0.00490.4747-0.0670.2931-25.3224-36.9039-19.8362
40.5285-0.21640.39070.23680.26221.27960.52690.2170.2118-0.21510.0126-0.38360.93840.5410.09960.12130.07980.01820.5045-0.12540.48581.2794-30.8492-5.4297
50.7184-0.3386-0.69940.81310.41351.49540.03630.11480.0596-0.02160.0015-0.10770.12830.3972-00.2857-0.01960.03760.3916-0.02410.3307-8.5079-30.5246-12.4451
60.6204-0.1531-0.58860.20070.55860.94430.1719-0.03310.1585-0.1286-0.0124-0.1334-0.20270.127-0.00080.2917-0.0660.03840.35510.00930.3614-10.3966-20.9364-10.4312
70.3624-0.29650.26830.31460.29160.32520.1531-0.37150.01710.091-0.02280.0408-0.07590.68910.00020.3564-0.0639-0.03530.4637-0.02180.3873-10.2176-25.318716.8077
8-0.02620.0486-0.04650.0949-0.02180.0305-0.0980.2614-0.02090.09020.1259-0.1053-0.09030.0208-00.2765-0.04840.03130.39550.02340.2771-25.947-17.4838-16.5767
90.54870.4579-0.58560.1927-0.3910.33920.0836-0.05910.04640.2263-0.059-0.03350.21690.363900.39760.0371-0.05580.39-0.02260.3475-7.3292-31.06755.2043
100.0724-0.13150.05090.01810.01340.0394-0.2762-0.15380.00230.45550.07770.28610.32340.1134-0.00010.470.00540.070.2935-0.020.3268-16.3765-40.02150.5558
110.0622-0.2146-0.27610.01690.05090.3708-0.21920.2470.07180.4381-0.01760.15230.21610.19280.00020.3822-0.0470.07760.289-0.02030.3245-23.5516-35.34931.7119
120.3295-0.0047-0.0566-0.0330.06880.18250.1364-0.0177-0.3776-0.08580.16930.24170.64030.14310.00770.42660.0449-0.02390.331-0.01610.3616-14.3553-30.812710.1755
130.1277-0.2518-0.06020.0865-0.10070.5149-0.01090.0050.08-0.737-0.1297-0.0062-0.0025-0.183-0.00030.3146-0.0530.04120.3059-0.01170.3198-26.8797-32.2831-9.7677
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 125 through 137 )A125 - 137
2X-RAY DIFFRACTION2chain 'A' and (resid 138 through 151 )A138 - 151
3X-RAY DIFFRACTION3chain 'A' and (resid 152 through 163 )A152 - 163
4X-RAY DIFFRACTION4chain 'A' and (resid 164 through 181 )A164 - 181
5X-RAY DIFFRACTION5chain 'A' and (resid 182 through 245 )A182 - 245
6X-RAY DIFFRACTION6chain 'A' and (resid 246 through 283 )A246 - 283
7X-RAY DIFFRACTION7chain 'A' and (resid 284 through 297 )A284 - 297
8X-RAY DIFFRACTION8chain 'B' and (resid 317 through 328 )B317 - 328
9X-RAY DIFFRACTION9chain 'B' and (resid 329 through 347 )B329 - 347
10X-RAY DIFFRACTION10chain 'B' and (resid 348 through 360 )B348 - 360
11X-RAY DIFFRACTION11chain 'B' and (resid 361 through 377 )B361 - 377
12X-RAY DIFFRACTION12chain 'B' and (resid 378 through 390 )B378 - 390
13X-RAY DIFFRACTION13chain 'B' and (resid 391 through 404 )B391 - 404

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