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- PDB-4k69: Crystal Structure of Human Chymase in Complex with Fragment Linke... -

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Basic information

Entry
Database: PDB / ID: 4k69
TitleCrystal Structure of Human Chymase in Complex with Fragment Linked Benzimidazolone Inhibitor: (3S)-3-{3-[(6-bromo-2-oxo-2,3-dihydro-1H-indol-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}hexanoic acid
ComponentsChymase
KeywordsHYDROLASE/HYDROLASE INHIBITOR / serine protease / glycosylated / Mast cells / secreted / HYDROLASE-HYDROLASE INHIBITOR complex
Function / homology
Function and homology information


chymase / basement membrane disassembly / cytokine precursor processing / midbrain development / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / serine-type peptidase activity / secretory granule ...chymase / basement membrane disassembly / cytokine precursor processing / midbrain development / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / angiotensin maturation / Metabolism of Angiotensinogen to Angiotensins / serine-type peptidase activity / secretory granule / cellular response to glucose stimulus / peptide binding / protein catabolic process / Signaling by SCF-KIT / cytoplasmic ribonucleoprotein granule / positive regulation of angiogenesis / regulation of inflammatory response / collagen-containing extracellular matrix / endopeptidase activity / intracellular membrane-bounded organelle / serine-type endopeptidase activity / extracellular space / extracellular region / cytoplasm / cytosol
Similarity search - Function
Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases ...Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin domain profile. / Serine proteases, trypsin family, serine active site. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Trypsin-like serine proteases / Thrombin, subunit H / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.5 Å
AuthorsCollins, B.K. / Padyana, A.K.
Citation
Journal: J.Med.Chem. / Year: 2013
Title: Discovery of Potent, Selective Chymase Inhibitors via Fragment Linking Strategies.
Authors: Taylor, S.J. / Padyana, A.K. / Abeywardane, A. / Liang, S. / Hao, M.H. / De Lombaert, S. / Proudfoot, J. / Farmer, B.S. / Li, X. / Collins, B. / Martin, L. / Albaugh, D.R. / Hill-Drzewi, M. ...Authors: Taylor, S.J. / Padyana, A.K. / Abeywardane, A. / Liang, S. / Hao, M.H. / De Lombaert, S. / Proudfoot, J. / Farmer, B.S. / Li, X. / Collins, B. / Martin, L. / Albaugh, D.R. / Hill-Drzewi, M. / Pullen, S.S. / Takahashi, H.
#1: Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Benzimidazolone as potent chymase inhibitor: modulation of reactive metabolite formation in the hydrophobic (P1) region.
Authors: Lo, H.Y. / Nemoto, P.A. / Kim, J.M. / Hao, M.H. / Qian, K.C. / Farrow, N.A. / Albaugh, D.R. / Fowler, D.M. / Schneiderman, R.D. / Michael August, E. / Martin, L. / Hill-Drzewi, M. / Pullen, ...Authors: Lo, H.Y. / Nemoto, P.A. / Kim, J.M. / Hao, M.H. / Qian, K.C. / Farrow, N.A. / Albaugh, D.R. / Fowler, D.M. / Schneiderman, R.D. / Michael August, E. / Martin, L. / Hill-Drzewi, M. / Pullen, S.S. / Takahashi, H. / De Lombaert, S.
History
DepositionApr 15, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 29, 2013Provider: repository / Type: Initial release
Revision 1.1Jul 3, 2013Group: Database references
Revision 1.2Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms / struct_conn / struct_ref_seq_dif / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_role / _struct_ref_seq_dif.details
Description: Carbohydrate remediation / Provider: repository / Type: Remediation

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Chymase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8165
Polymers24,9921
Non-polymers8244
Water5,026279
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)74.365, 74.365, 49.474
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

#1: Protein Chymase / Alpha-chymase / Mast cell protease I


Mass: 24991.857 Da / Num. of mol.: 1 / Fragment: UNP residues 22-247
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CMA1, CYH, CYM / Plasmid: pDest1393 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P23946, chymase
#2: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn
#3: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#4: Chemical ChemComp-1P9 / (3S)-3-{3-[(6-bromo-2-oxo-2,3-dihydro-1H-indol-4-yl)methyl]-2-oxo-2,3-dihydro-1H-benzimidazol-1-yl}hexanoic acid


Mass: 472.332 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H22BrN3O4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 279 / 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: 2.74 Å3/Da / Density % sol: 55.06 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 8
Details: 26-33% PEG8000, 0.1 M Tris, pH 8.0, 2 mM zinc sulfate, VAPOR DIFFUSION, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E SUPERBRIGHT / Wavelength: 1.5418 Å
DetectorType: RIGAKU SATURN 92 / Detector: CCD / Date: Sep 5, 2006 / Details: VERIMAX HF
RadiationMonochromator: Ni FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.5→74.36 Å / Num. obs: 43154 / % possible obs: 99.4 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 2.87 % / Rmerge(I) obs: 0.06 / Χ2: 0.93 / Net I/σ(I): 11.5 / Scaling rejects: 938
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allΧ2% possible all
1.5-1.552.210.2392.7935842410.7798.1
1.55-1.622.290.193.2978442690.7698.9
1.62-1.692.410.1584.11030842790.7799.4
1.69-1.782.530.1374.71089643060.7199.7
1.78-1.892.70.1254.71167143200.72100
1.89-2.042.860.1246.11239643330.82100
2.04-2.243.090.0918.71344643410.76100
2.24-2.573.350.0812.21460143450.86100
2.57-3.233.630.047201598943551.0199.8
3.23-74.363.620.04333.71643943651.6398.2

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Processing

Software
NameVersionClassificationNB
d*TREK9.6Ldata reduction
PHENIX1.8_1069refinement
PDB_EXTRACT3.11data extraction
d*TREKdata scaling
CNXphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.5→33.257 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.8489 / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.34 / Phase error: 22.37 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2231 2159 5.01 %RANDOM
Rwork0.1971 ---
obs0.1984 43069 99.22 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 49.46 Å2 / Biso mean: 20.2389 Å2 / Biso min: 10.15 Å2
Refinement stepCycle: LAST / Resolution: 1.5→33.257 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1666 0 46 279 1991
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0061788
X-RAY DIFFRACTIONf_angle_d1.1082421
X-RAY DIFFRACTIONf_chiral_restr0.079266
X-RAY DIFFRACTIONf_plane_restr0.005308
X-RAY DIFFRACTIONf_dihedral_angle_d14.217660
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 15

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.5-1.5350.24791490.21692692284198
1.535-1.57330.22131290.20932674280399
1.5733-1.61590.21361270.19262739286699
1.6159-1.66340.23851650.19062651281699
1.6634-1.71710.22961390.182927672906100
1.7171-1.77850.22541480.191127112859100
1.7785-1.84970.19091440.1927382882100
1.8497-1.93390.31851420.29292733287599
1.9339-2.03580.23121540.202327272881100
2.0358-2.16330.19621520.182327262878100
2.1633-2.33030.27461320.252227722904100
2.3303-2.56480.23491360.183927542890100
2.5648-2.93570.22381470.197627492896100
2.9357-3.69790.211450.18122761290699
3.6979-33.26520.19311500.17492716286696

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