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- PDB-9gcd: CRYSTAL STRUCTURE OF HUMAN CHYMASE IN COMPLEX WITH Fulacimstat (C... -

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Basic information

Entry
Database: PDB / ID: 9gcd
TitleCRYSTAL STRUCTURE OF HUMAN CHYMASE IN COMPLEX WITH Fulacimstat (COMPOUND86)
ComponentsChymase
KeywordsHYDROLASE / SERINE PROTEASE / GLYCOSYLATED / MAST CELLS / SECRETED / HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


chymase / basement membrane disassembly / cytokine precursor processing / peptide metabolic process / midbrain development / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / serine-type peptidase activity ...chymase / basement membrane disassembly / cytokine precursor processing / peptide metabolic process / midbrain development / Activation of Matrix Metalloproteinases / extracellular matrix disassembly / Metabolism of Angiotensinogen to Angiotensins / angiotensin maturation / serine-type peptidase activity / protein maturation / peptide binding / secretory granule / protein catabolic process / cellular response to glucose stimulus / Signaling by SCF-KIT / cytoplasmic ribonucleoprotein granule / positive regulation of angiogenesis / regulation of inflammatory response / : / endopeptidase activity / serine-type endopeptidase activity / extracellular space / extracellular region / cytosol
Similarity search - Function
Serine proteases, trypsin family, histidine active site / Serine proteases, trypsin family, serine active site / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan, chymotrypsin-like fold / Peptidase S1, PA clan
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.798 Å
AuthorsSchaefer, M. / Fuerstner, C.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery and Preclinical Characterization of Fulacimstat (BAY 1142524), a Potent and Selective Chymase Inhibitor As a New Profibrinolytic Approach for Safe Thrombus Resolution.
Authors: Furstner, C. / Ackerstaff, J. / Meier, H. / Straub, A. / Mittendorf, J. / Schamberger, J. / Schafer, M. / Borngen, K. / Jorissen, H. / Zubov, D. / Zimmermann, K. / Tersteegen, A. / Geiss, V. ...Authors: Furstner, C. / Ackerstaff, J. / Meier, H. / Straub, A. / Mittendorf, J. / Schamberger, J. / Schafer, M. / Borngen, K. / Jorissen, H. / Zubov, D. / Zimmermann, K. / Tersteegen, A. / Geiss, V. / Hartmann, E. / Albrecht-Kupper, B. / D'Orleans-Juste, P. / Lapointe, C. / Vincent, L. / Heitmeier, S. / Tinel, H.
History
DepositionAug 1, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.1Apr 9, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
AAA: Chymase
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,7465
Polymers25,0201
Non-polymers1,7264
Water4,540252
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint-6 kcal/mol
Surface area11310 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.080, 74.080, 49.790
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

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Protein , 1 types, 1 molecules AAA

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


Mass: 25019.871 Da / Num. of mol.: 1 / Mutation: F127K, V208A, R235Q
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CMA1, CYH, CYM
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P23946, chymase

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Sugars , 2 types, 2 molecules

#2: Polysaccharide alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1- ...alpha-D-mannopyranose-(1-6)-beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 748.682 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DManpa1-6DManpb1-4DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/3,4,3/[a2122h-1b_1-5_2*NCC/3=O][a1122h-1b_1-5][a1122h-1a_1-5]/1-1-2-3/a4-b1_b4-c1_c6-d1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{[(4+1)][b-D-Manp]{[(6+1)][a-D-Manp]{}}}}LINUCSPDB-CARE
#3: Polysaccharide 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose


Type: oligosaccharide / Mass: 424.401 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
DescriptorTypeProgram
DGlcpNAcb1-4DGlcpNAcb1-ROHGlycam Condensed SequenceGMML 1.0
WURCS=2.0/1,2,1/[a2122h-1b_1-5_2*NCC/3=O]/1-1/a4-b1WURCSPDB2Glycan 1.1.0
[][D-1-deoxy-GlcpNAc]{[(4+1)][b-D-GlcpNAc]{}}LINUCSPDB-CARE

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Non-polymers , 3 types, 254 molecules

#4: Chemical ChemComp-A1IJ2 / 1-(3-methyl-2-oxidanylidene-1,3-benzoxazol-6-yl)-2,4-bis(oxidanylidene)-3-[(1R)-4-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]pyrimidine-5-carboxylic acid


Mass: 487.385 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H16F3N3O6 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Zn
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 252 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.73 Å3/Da / Density % sol: 54.95 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8 / Details: 0.01M ZnCl2, 0.1M TRIS at pH 8 and 20% PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 HF / Wavelength: 1.54187 Å
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Nov 30, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54187 Å / Relative weight: 1
ReflectionResolution: 1.79→41.32 Å / Num. obs: 24967 / % possible obs: 98.2 % / Redundancy: 2.6 % / Rmerge(I) obs: 0.051 / Net I/σ(I): 14.3
Reflection shellResolution: 1.79→1.89 Å / Rmerge(I) obs: 0.318 / Mean I/σ(I) obs: 3 / Num. unique obs: 3377

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Processing

Software
NameVersionClassification
REFMAC5.8.0267refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.798→29.718 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.926 / Cross valid method: FREE R-VALUE / ESU R: 0.118 / ESU R Free: 0.114
Details: Hydrogens have been used if present in the input file
RfactorNum. reflection% reflection
Rfree0.212 1273 5.107 %
Rwork0.1778 23652 -
all0.179 --
obs-24925 98.639 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 33.036 Å2
Baniso -1Baniso -2Baniso -3
1-0.031 Å20 Å20 Å2
2--0.031 Å20 Å2
3----0.062 Å2
Refinement stepCycle: LAST / Resolution: 1.798→29.718 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1666 0 114 252 2032
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0121826
X-RAY DIFFRACTIONr_angle_refined_deg1.6031.7412475
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.7925210
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.62920.83384
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.38415294
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7831513
X-RAY DIFFRACTIONr_chiral_restr0.0830.2252
X-RAY DIFFRACTIONr_gen_planes_refined0.0120.021313
X-RAY DIFFRACTIONr_nbd_refined0.2710.2866
X-RAY DIFFRACTIONr_nbtor_refined0.3140.21249
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1810.2204
X-RAY DIFFRACTIONr_metal_ion_refined0.0490.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2420.247
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.2710.230
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined0.0470.21
X-RAY DIFFRACTIONr_mcbond_it2.1412.83855
X-RAY DIFFRACTIONr_mcangle_it2.7414.2331060
X-RAY DIFFRACTIONr_scbond_it3.8363.409971
X-RAY DIFFRACTIONr_scangle_it5.7744.921415
X-RAY DIFFRACTIONr_lrange_it7.13442.3272899
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.798-1.8450.321860.30116840.30218630.8460.85795.0080.283
1.845-1.8950.263990.2416770.24117800.8850.90199.77530.22
1.895-1.950.217780.20416760.20417560.9310.92799.88610.184
1.95-2.010.2031000.18216280.18317290.9410.94199.94220.16
2.01-2.0750.232880.17815530.18116430.9280.9499.87830.157
2.075-2.1480.22820.17215030.17415880.930.94499.81110.153
2.148-2.2280.226790.17514710.17715520.9210.94599.87110.156
2.228-2.3190.216810.16613880.16914700.9370.95399.9320.148
2.319-2.4210.186670.15913680.1614350.9540.961000.143
2.421-2.5390.212800.17112960.17413790.9420.9599.78240.154
2.539-2.6750.205530.1812290.18112840.9270.94399.84420.165
2.675-2.8360.238670.17811780.18112500.9350.94699.60.163
2.836-3.030.174690.17110760.17211550.9540.95899.13420.161
3.03-3.2690.203520.17210140.17310840.9460.9698.33950.163
3.269-3.5770.212470.179400.17210050.9450.96198.2090.167
3.577-3.9920.198400.1518470.1539090.9560.96897.57980.149
3.992-4.5960.18340.1487450.1498130.9590.96895.8180.145
4.596-5.5960.157270.1616290.1616880.9610.96795.34880.16
5.596-7.7770.238370.2144680.2165410.9420.94993.34570.211
7.777-29.7180.25370.2272820.2283340.9270.94786.52690.225

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