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- PDB-5mtk: Crystal structure of human Caspase-1 with (3S,6S,10aS)-N-((2S,3S)... -

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Basic information

Entry
Database: PDB / ID: 5mtk
TitleCrystal structure of human Caspase-1 with (3S,6S,10aS)-N-((2S,3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)-6-(isoquinoline-1-carboxamido)-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxamide (PGE-3935199)
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-N7N / Caspase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.53 Å
AuthorsBrethon, A. / Chantalat, L. / Christin, O. / Clary, L. / Fournier, J.F. / Gastreich, M. / Harris, C. / Pascau, J. / Isabet, T. / Rodeschin, V. ...Brethon, A. / Chantalat, L. / Christin, O. / Clary, L. / Fournier, J.F. / Gastreich, M. / Harris, C. / Pascau, J. / Isabet, T. / Rodeschin, V. / Thoreau, E. / Roche, D.
CitationJournal: To Be Published
Title: Playing against the odds: scaffold hopping from 3D-fragments
Authors: Brethon, A. / Chantalat, L. / Christin, O. / Clary, L. / Fournier, J.F. / Gastreich, M. / Harris, C. / Pascau, J. / Isabet, T. / Rodeschin, V. / Thoreau, E. / Roche, D.
History
DepositionJan 9, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 28, 2018Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)30,8743
Polymers30,3912
Non-polymers4831
Water30617
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-35 kcal/mol
Surface area13290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.589, 64.589, 161.102
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212

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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: 20001.033 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: 10389.950 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-N7N / (3~{S})-3-[[(3~{S},6~{S},10~{a}~{S})-6-(isoquinolin-1-ylcarbonylamino)-5-oxidanylidene-2,3,6,7,8,9,10,10~{a}-octahydro-1~{H}-pyrrolo[1,2-a]azocin-3-yl]carbonylamino]-4-oxidanyl-butanoic acid


Mass: 482.529 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H30N4O6
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 17 / 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: 2.76 Å3/Da / Density % sol: 55.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES (pH 7.4), 2 M (NH4)2SO4 and 25 mM DTT

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.53→50.39 Å / Num. obs: 11888 / % possible obs: 98.5 % / Redundancy: 5.9 % / Biso Wilson estimate: 66.7 Å2 / Net I/σ(I): 11
Reflection shellResolution: 2.53→2.62 Å / Redundancy: 5.2 % / Mean I/σ(I) obs: 1.9 / Num. unique obs: 1061 / % possible all: 92.4

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Processing

Software
NameVersionClassification
BUSTER2.10.2refinement
SCALAdata scaling
Cootmodel building
PHASERphasing
RefinementResolution: 2.53→15 Å / Cor.coef. Fo:Fc: 0.818 / Cor.coef. Fo:Fc free: 0.759 / Rfactor Rfree error: 0 / SU R Cruickshank DPI: 0.475 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.505 / SU Rfree Blow DPI: 0.32 / SU Rfree Cruickshank DPI: 0.318
RfactorNum. reflection% reflectionSelection details
Rfree0.299 560 4.76 %RANDOM
Rwork0.243 ---
obs0.246 11764 98.2 %-
Displacement parametersBiso mean: 62.39 Å2
Baniso -1Baniso -2Baniso -3
1-8.8753 Å20 Å20 Å2
2--8.8753 Å20 Å2
3----17.7506 Å2
Refine analyzeLuzzati coordinate error obs: 0 Å
Refinement stepCycle: 1 / Resolution: 2.53→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2010 0 35 17 2062
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092099HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.972830HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d758SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes50HARMONIC2
X-RAY DIFFRACTIONt_gen_planes316HARMONIC5
X-RAY DIFFRACTIONt_it2099HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion1.87
X-RAY DIFFRACTIONt_other_torsion19.34
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion280SEMIHARMONIC5
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_contact2181SEMIHARMONIC4
LS refinement shellResolution: 2.53→2.77 Å / Rfactor Rfree error: 0 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.346 129 4.86 %
Rwork0.259 2526 -
all0.264 2655 -
obs--94.68 %
Refinement TLS params.Method: refined / Origin x: -0.3776 Å / Origin y: -17.4001 Å / Origin z: 5.6499 Å
111213212223313233
T0.0194 Å2-0.0322 Å2-0.0214 Å2-0.0214 Å20.0412 Å2---0.2162 Å2
L3.1656 °2-0.7115 °20.598 °2-2.6237 °2-1.3619 °2--2.4024 °2
S-0.0019 Å °0.2186 Å °-0.3404 Å °0.4517 Å °-0.0153 Å °-0.0748 Å °0.1881 Å °0.4502 Å °0.0172 Å °
Refinement TLS groupSelection details: { *|* }

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