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- PDB-3ns7: Succinic Acid Amides as P2-P3 Replacements for Inhibitors of Inte... -

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Basic information

Entry
Database: PDB / ID: 3ns7
TitleSuccinic Acid Amides as P2-P3 Replacements for Inhibitors of Interleukin-1beta Converting Enzyme (ICE or Caspase 1)
Components(Caspase-1Caspase 1) x 2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / cysteine protease / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


caspase-1 / protease inhibitor complex / AIM2 inflammasome complex assembly / The AIM2 inflammasome / AIM2 inflammasome complex / IPAF inflammasome complex / The IPAF inflammasome / NLRP1 inflammasome complex / icosanoid biosynthetic process / cytokine precursor processing ...caspase-1 / protease inhibitor complex / AIM2 inflammasome complex assembly / The AIM2 inflammasome / AIM2 inflammasome complex / IPAF inflammasome complex / The IPAF inflammasome / NLRP1 inflammasome complex / icosanoid biosynthetic process / cytokine precursor processing / canonical inflammasome complex / positive regulation of interleukin-18 production / NLRP3 inflammasome complex / caspase binding / osmosensory signaling pathway / CARD domain binding / positive regulation of tumor necrosis factor-mediated signaling pathway / Interleukin-1 processing / Interleukin-37 signaling / pattern recognition receptor signaling pathway / cellular response to organic substance / signaling receptor ligand precursor processing / TP53 Regulates Transcription of Caspase Activators and Caspases / pyroptosis / cysteine-type endopeptidase activator activity involved in apoptotic process / positive regulation of cysteine-type endopeptidase activity involved in apoptotic process / protein autoprocessing / protein maturation / The NLRP3 inflammasome / Pyroptosis / Purinergic signaling in leishmaniasis infection / positive regulation of interleukin-1 beta production / NOD1/2 Signaling Pathway / kinase binding / positive regulation of inflammatory response / cellular response to type II interferon / cellular response to mechanical stimulus / SARS-CoV-1 activates/modulates innate immune responses / regulation of inflammatory response / defense response to virus / regulation of apoptotic process / positive regulation of canonical NF-kappaB signal transduction / endopeptidase activity / cellular response to lipopolysaccharide / microtubule / defense response to bacterium / cysteine-type endopeptidase activity / apoptotic process / nucleolus / signal transduction / protein-containing complex / proteolysis / identical protein binding / plasma membrane / cytosol / cytoplasm
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
(3S)-4-HYDROXY-3-{[(2S)-4-{[2-(2-METHYL-1H-BENZIMIDAZOL-1-YL)ETHYL]AMINO}-2-(1-METHYLETHYL)-4-OXOBUTANOYL]AMINO}BUTANOIC ACID / Chem-3NS / Caspase-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsGalatsis, P.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2010
Title: Succinic acid amides as P2-P3 replacements for inhibitors of interleukin-1beta converting enzyme (ICE or caspase 1).
Authors: Galatsis, P. / Caprathe, B. / Gilmore, J. / Thomas, A. / Linn, K. / Sheehan, S. / Harter, W. / Kostlan, C. / Lunney, E. / Stankovic, C. / Rubin, J. / Brady, K. / Allen, H. / Talanian, R.
History
DepositionJul 1, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 17, 2011Provider: repository / Type: Initial release
Revision 1.1Dec 12, 2012Group: Other
Revision 1.2Nov 8, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_atoms / software / Item: _software.classification / _software.name
Revision 1.3Dec 27, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)28,9753
Polymers28,5572
Non-polymers4181
Water84747
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5160 Å2
ΔGint-29 kcal/mol
Surface area12630 Å2
MethodPISA
2
A: Caspase-1
B: Caspase-1
hetero molecules

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


Theoretical massNumber of molelcules
Total (without water)57,9516
Polymers57,1144
Non-polymers8372
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area16140 Å2
ΔGint-82 kcal/mol
Surface area19440 Å2
MethodPISA
Unit cell
Length a, b, c (Å)63.950, 63.950, 158.550
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 / 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 / ICE / p45 / Caspase-1 subunit p20 / Caspase-1 subunit p10


Mass: 18298.098 Da / Num. of mol.: 1 / Fragment: UNP residues 136-297
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP1, IL1BC, IL1BCE / Plasmid: pACYC177 / Production host: Escherichia coli (E. coli) / References: UniProt: P29466, caspase-1
#2: Protein Caspase-1 / 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 / ICE / p45 / Caspase-1 subunit p20 / Caspase-1 subunit p10


Mass: 10258.755 Da / Num. of mol.: 1 / Fragment: UNP residues 317-404
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CASP1, IL1BC, IL1BCE / Plasmid: pACYC177 / Production host: Escherichia coli (E. coli) / References: UniProt: P29466, caspase-1
#3: Chemical ChemComp-3NS / (3S)-4-hydroxy-3-{[(2S)-4-{[2-(2-methyl-1H-benzimidazol-1-yl)ethyl]amino}-2-(1-methylethyl)-4-oxobutanoyl]amino}butanoic acid


Type: peptide-like, Peptide-like / Class: CASPASE inhibitor / Mass: 418.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30N4O5
References: (3S)-4-HYDROXY-3-{[(2S)-4-{[2-(2-METHYL-1H-BENZIMIDAZOL-1-YL)ETHYL]AMINO}-2-(1-METHYLETHYL)-4-OXOBUTANOYL]AMINO}BUTANOIC ACID
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 47 / Source method: isolated from a natural source / Formula: H2O
Compound detailsUPON REACTION THE INHIBITOR COVALENTLY BINDS TO THE SG ATOM OF CYS 285 OF THE ENZYME (CHAIN A) ...UPON REACTION THE INHIBITOR COVALENTLY BINDS TO THE SG ATOM OF CYS 285 OF THE ENZYME (CHAIN A) FORMING A TETRAHEDRAL HEMITHIOACETYL.

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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: 2.84 Å3/Da / Density % sol: 56.66 %
Crystal growTemperature: 276 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 276K

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Data collection

DiffractionMean temperature: 297 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.54 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Aug 7, 1999 / Details: mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.6→25 Å / Num. all: 11574 / Num. obs: 10574 / % possible obs: 98.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 0 / Redundancy: 3.93 % / Rsym value: 0.123 / Net I/σ(I): 11.78
Reflection shellResolution: 2.6→2.8 Å / Redundancy: 4 % / Rmerge(I) obs: 0.569 / Mean I/σ(I) obs: 2.4 / Num. unique all: 2043 / % possible all: 98.2

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Processing

Software
NameVersionClassification
CrystalCleardata collection
X-PLORmodel building
X-PLORrefinement
XDSdata reduction
MAR345SCALEdata collection
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.6→25 Å / σ(F): 2 / Stereochemistry target values: Engh & Huber
Details: STRUCTURE FACTOR VALIDATION DOES NOT YIELD GOOD AGREEMENT BETWEEN THE REPORTED AND CALCULATED R VALUES. AUTHORS STATES THAT THE STRUCTURE WAS DEPOSITED SEVERAL YEARS AGO IN AN INTERNAL ...Details: STRUCTURE FACTOR VALIDATION DOES NOT YIELD GOOD AGREEMENT BETWEEN THE REPORTED AND CALCULATED R VALUES. AUTHORS STATES THAT THE STRUCTURE WAS DEPOSITED SEVERAL YEARS AGO IN AN INTERNAL DATABASE AT THE MICHIGAN LABS OF PFIZER, INC. WITH THE CLOSURE OF THAT SITE, THE FILES SUBMITTED TO PDB ARE THE ONLY DATA THEY HAVE FOR THIS STRUCTURE.
RfactorNum. reflectionSelection details
Rwork0.188 --
all0.214 11574 -
obs0.214 10574 -
Rfree-1000 Random
Refinement stepCycle: LAST / Resolution: 2.6→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1996 0 30 47 2073

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