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- PDB-6f6r: Crystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-... -

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Basic information

Entry
Database: PDB / ID: 6f6r
TitleCrystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-(quinoxalin-2-ylamino)-benzamide
Components(Caspase-1) x 2
KeywordsHYDROLASE / caspase-1 / nanomolar inhibitor / inflammatory diseases / sp3 hybridization
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 / Caspase-like / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Rossmann fold - #1460 / 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 recruitment domain / Caspase-like / CARD domain / CARD caspase recruitment domain profile. / Caspase recruitment domain / Rossmann fold - #1460 / 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 / Alpha-Beta Plaits / Rossmann fold / 2-Layer Sandwich / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-CVE / Caspase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsFournier, J.F. / Clary, L. / Chambon, S. / Dumais, L. / Harris, C.S. / Millois-Barbuis, C. / Pierre, R. / Talano, S. / Thoreau, E. / Aubert, J. ...Fournier, J.F. / Clary, L. / Chambon, S. / Dumais, L. / Harris, C.S. / Millois-Barbuis, C. / Pierre, R. / Talano, S. / Thoreau, E. / Aubert, J. / Aurelly, M. / Bouix-Peter, C. / Brethon, A. / Chantalat, L. / Christin, O. / Comino, C. / El-Bazbouz, G. / Ghilini, A.L. / Isabet, T. / Lardy, C. / Luzy, A.P. / Mathieu, C. / Mebrouk, K. / Orfila, D. / Pascau, J. / Reverse, K. / Roche, D. / Rodeschini, V. / Hennequin, L.F.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.
Authors: Fournier, J.F. / Clary, L. / Chambon, S. / Dumais, L. / Harris, C.S. / Millois, C. / Pierre, R. / Talano, S. / Thoreau, E. / Aubert, J. / Aurelly, M. / Bouix-Peter, C. / Brethon, A. / ...Authors: Fournier, J.F. / Clary, L. / Chambon, S. / Dumais, L. / Harris, C.S. / Millois, C. / Pierre, R. / Talano, S. / Thoreau, E. / Aubert, J. / Aurelly, M. / Bouix-Peter, C. / Brethon, A. / Chantalat, L. / Christin, O. / Comino, C. / El-Bazbouz, G. / Ghilini, A.L. / Isabet, T. / Lardy, C. / Luzy, A.P. / Mathieu, C. / Mebrouk, K. / Orfila, D. / Pascau, J. / Reverse, K. / Roche, D. / Rodeschini, V. / Hennequin, L.F.
History
DepositionDec 6, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 2, 2018Provider: repository / Type: Initial release
Revision 1.1May 23, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.name

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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)31,0294
Polymers30,3722
Non-polymers6582
Water4,558253
1
A: Caspase-1
B: Caspase-1
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)62,0598
Polymers60,7444
Non-polymers1,3154
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z1
Buried area18230 Å2
ΔGint-125 kcal/mol
Surface area22290 Å2
MethodPISA
2


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6230 Å2
ΔGint-53 kcal/mol
Surface area14030 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.140, 64.140, 165.850
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Components on special symmetry positions
IDModelComponents
11B-501-

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: 20113.053 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-CVE / (3~{S})-3-[[(2~{R})-2-[3-methyl-2,6-bis(oxidanylidene)-5-[[4-(quinoxalin-2-ylamino)phenyl]carbonylamino]pyrimidin-1-yl]propanoyl]amino]-4-oxidanyl-butanoic acid


Mass: 561.546 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H27N7O7
#4: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 253 / Source method: isolated from a natural source / Formula: H2O

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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: 4.63 Å3/Da / Density % sol: 73.43 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES (pH7.4), 2 M (NH4)2SO4 and 25 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.97857 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97857 Å / Relative weight: 1
ReflectionResolution: 1.8→50 Å / Num. obs: 32900 / % possible obs: 99.4 % / Redundancy: 7.14 % / Biso Wilson estimate: 31.25 Å2 / CC1/2: 0.999 / Net I/σ(I): 14.61
Reflection shellResolution: 1.8→1.91 Å / Redundancy: 7.25 % / Mean I/σ(I) obs: 1.46 / Num. unique obs: 5188 / CC1/2: 0.749 / % possible all: 98.8

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Processing

Software
NameVersionClassification
BUSTER2.10.3refinement
XDSdata processing
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→43.75 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.938 / SU R Cruickshank DPI: 0.102 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.111 / SU Rfree Blow DPI: 0.107 / SU Rfree Cruickshank DPI: 0.101
RfactorNum. reflection% reflectionSelection details
Rfree0.205 1644 5 %RANDOM
Rwork0.173 ---
obs0.174 32881 99.5 %-
Displacement parametersBiso mean: 41.04 Å2
Baniso -1Baniso -2Baniso -3
1--4.8437 Å20 Å20 Å2
2---4.8437 Å20 Å2
3---9.6874 Å2
Refine analyzeLuzzati coordinate error obs: 0.23 Å
Refinement stepCycle: 1 / Resolution: 1.8→43.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2114 0 46 253 2413
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012263HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.053064HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d816SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes54HARMONIC2
X-RAY DIFFRACTIONt_gen_planes359HARMONIC5
X-RAY DIFFRACTIONt_it2263HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.71
X-RAY DIFFRACTIONt_other_torsion15.81
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion300SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2908SEMIHARMONIC4
LS refinement shellResolution: 1.8→1.86 Å / Total num. of bins used: 16
RfactorNum. reflection% reflection
Rfree0.2573 147 4.97 %
Rwork0.2402 2810 -
all0.241 2957 -
obs--99.2 %
Refinement TLS params.Method: refined / Origin x: 14.2517 Å / Origin y: 30.1142 Å / Origin z: -6.9184 Å
111213212223313233
T0.1569 Å2-0.0058 Å2-0.0118 Å2-0.2003 Å20.0167 Å2--0.1469 Å2
L0.6824 °2-0.4036 °20.5372 °2-1.0359 °2-0.5502 °2--1.6209 °2
S-0.0381 Å °0.0667 Å °0.002 Å °0.0718 Å °0.045 Å °0.0554 Å °-0.1314 Å °-0.1662 Å °-0.0069 Å °
Refinement TLS groupSelection details: { A|* },{ B|* },

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