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- PDB-1nmq: Extendend Tethering: In Situ Assembly of Inhibitors -

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Basic information

Entry
Database: PDB / ID: 1nmq
TitleExtendend Tethering: In Situ Assembly of Inhibitors
ComponentsCaspase-3Caspase 3
KeywordsAPOPTOSIS / HYDROLASE / Caspase-3 / Tethering / Small molecule complex
Function / homology
Function and homology information


caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis ...caspase-3 / Stimulation of the cell death response by PAK-2p34 / phospholipase A2 activator activity / anterior neural tube closure / intrinsic apoptotic signaling pathway in response to osmotic stress / leukocyte apoptotic process / positive regulation of pyroptotic inflammatory response / glial cell apoptotic process / NADE modulates death signalling / luteolysis / response to cobalt ion / cysteine-type endopeptidase activity involved in apoptotic signaling pathway / death-inducing signaling complex / cyclin-dependent protein serine/threonine kinase inhibitor activity / cellular response to staurosporine / Apoptosis induced DNA fragmentation / Apoptotic cleavage of cell adhesion proteins / cysteine-type endopeptidase activity involved in execution phase of apoptosis / Caspase activation via Dependence Receptors in the absence of ligand / death receptor binding / SMAC, XIAP-regulated apoptotic response / axonal fasciculation / Activation of caspases through apoptosome-mediated cleavage / Signaling by Hippo / SMAC (DIABLO) binds to IAPs / SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes / cysteine-type endopeptidase activity involved in apoptotic process / fibroblast apoptotic process / execution phase of apoptosis / negative regulation of cytokine production / epithelial cell apoptotic process / platelet formation / Other interleukin signaling / positive regulation of amyloid-beta formation / pyroptotic inflammatory response / Apoptotic cleavage of cellular proteins / negative regulation of B cell proliferation / T cell homeostasis / negative regulation of activated T cell proliferation / neurotrophin TRK receptor signaling pathway / B cell homeostasis / protein maturation / negative regulation of cell cycle / response to X-ray / Caspase-mediated cleavage of cytoskeletal proteins / regulation of macroautophagy / response to amino acid / cell fate commitment / Pyroptosis / response to tumor necrosis factor / response to glucose / response to UV / response to glucocorticoid / keratinocyte differentiation / striated muscle cell differentiation / Degradation of the extracellular matrix / intrinsic apoptotic signaling pathway / erythrocyte differentiation / response to nicotine / apoptotic signaling pathway / hippocampus development / sensory perception of sound / protein catabolic process / regulation of protein stability / response to hydrogen peroxide / protein processing / neuron differentiation / response to wounding / positive regulation of neuron apoptotic process / response to estradiol / heart development / peptidase activity / neuron apoptotic process / protease binding / response to lipopolysaccharide / aspartic-type endopeptidase activity / response to hypoxia / learning or memory / response to xenobiotic stimulus / positive regulation of apoptotic process / cysteine-type endopeptidase activity / neuronal cell body / apoptotic process / DNA damage response / protein-containing complex binding / proteolysis / nucleoplasm / nucleus / cytosol / cytoplasm
Similarity search - Function
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 ...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 / Rossmann fold / 3-Layer(aba) Sandwich / Alpha Beta
Similarity search - Domain/homology
Chem-160 / Caspase-3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 Å
AuthorsErlanson, D.A. / Lam, J. / Wiesmann, C. / Luong, T.N. / Simmons, R.L. / DeLano, W. / Choong, I.C. / Flanagan, M. / Lee, D. / O'Brian, T.
Citation
#1: Journal: J.Med.Chem. / Year: 2002
Title: Identification of Potent and Selective Small-Molecule Inhibitors of Caspase-3 through the Use of Extended Tethering and Structure-Based Drug Design
Authors: Choong, I.C. / Lew, W. / Lee, D. / Pham, P. / Burdett, M.T. / Lam, J.W. / Wiesmann, C. / Luong, T.N. / Fahr, B. / O'Brian, T.
History
DepositionJan 10, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 11, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 16, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.end_auth_comp_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

Downloads & links

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Assembly

Deposited unit
A: Caspase-3
B: Caspase-3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)58,1984
Polymers57,0372
Non-polymers1,1612
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6380 Å2
ΔGint-33 kcal/mol
Surface area19260 Å2
MethodPISA
Unit cell
Length a, b, c (Å)68.858, 89.043, 96.531
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Cell settingorthorhombic
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31A
41B

NCS domain segments:

Ens-ID: 1 / Refine code: 3

Dom-IDComponent-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11ASPASPTHRTHRAA34 - 1746 - 146
21ASPASPTHRTHRBB34 - 1746 - 146
32HISHISHISHISAA185 - 277157 - 249
42HISHISHISHISBB185 - 277157 - 249

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Components

#1: Protein Caspase-3 / Caspase 3 / E.C.3.4.22.- / Apopain / Cysteine protease CPP32 / Yama protein / CPP-32 / CASP-3 / SREBP cleavage activity 1 / SCA-1


Mass: 28518.500 Da / Num. of mol.: 2 / Fragment: large subunit
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
References: UniProt: P42574, Hydrolases; Acting on peptide bonds (peptidases); Cysteine endopeptidases
#2: Chemical ChemComp-160 / 3-(3-{2-[(5-METHANESULFONYL-THIOPHENE-2-CARBONYL)-AMINO]-ETHYLDISULFANYLMETHYL}- BENZENESULFONYLAMINO)-4-OXO-PENTANOIC ACID / E.C.3.4.22.-


Mass: 580.738 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C20H24N2O8S5
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 2.63 Å3/Da / Density % sol: 52.8 %
Crystal grow
*PLUS
Temperature: 20 ℃ / pH: 8.5 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
15-10 mg/mlprotein1drop
210 mMTris1droppH8.5
3100 mMsodium citrate1reservoirpH5.9
44 %(v/v)glycerol1reservoir
510-20 %(w/v)PEG60001reservoir
610 mMdithiothreitol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: May 5, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→12 Å / Num. all: 23665 / % possible obs: 95.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rsym value: 0.104 / Net I/σ(I): 6.8
Reflection
*PLUS
Highest resolution: 2.4 Å / Lowest resolution: 20 Å / Rmerge(I) obs: 0.104

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Processing

Software
NameVersionClassification
d*TREKdata scaling
d*TREKdata reduction
AMoREphasing
REFMAC5refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1CP3

1cp3


Resolution: 2.4→20 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.894 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.29947 2238 10 %RANDOM
Rwork0.24113 ---
all0.24698 20098 --
obs0.24698 20098 93.87 %-
Solvent computationShrinkage radii: 0.8 Å / Solvent model: MASK
Displacement parametersBiso mean: 25.794 Å2
Baniso -1Baniso -2Baniso -3
1--1.14 Å20 Å20 Å2
2--3.26 Å20 Å2
3----2.12 Å2
Refinement stepCycle: LAST / Resolution: 2.4→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3854 0 70 100 4024
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0214004
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4111.9635384
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg3.5023470
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.65215740
X-RAY DIFFRACTIONr_chiral_restr0.0940.2574
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023016
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2610.31831
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1570.5343
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2180.329
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0770.53
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_mcbond_it3.2342.52362
X-RAY DIFFRACTIONr_mcangle_it5.06653810
X-RAY DIFFRACTIONr_scbond_it3.6572.51642
X-RAY DIFFRACTIONr_scangle_it5.34851574
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Dom-ID: 1 / Auth asym-ID: A / Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

NumberTypeRms dev position (Å)Weight position
952tight positional0.030.05
945loose positional0.185
952tight thermal0.090.5
945loose thermal2.2310
LS refinement shellResolution: 2.4→2.449 Å / Total num. of bins used: 25 /
RfactorNum. reflection
Rfree0.396 130
Rwork0.322 1215
Refinement
*PLUS
Highest resolution: 2.4 Å / Lowest resolution: 20 Å / Rfactor Rfree: 0.299 / Rfactor Rwork: 0.241
Solvent computation
*PLUS
Displacement parameters
*PLUS

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