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- PDB-9h79: Crystal structure of Thrombin in complex with a Chlorothiophene-b... -

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Basic information

Entry
Database: PDB / ID: 9h79
TitleCrystal structure of Thrombin in complex with a Chlorothiophene-based inhibitor, CP2, discovered by a novel rapid nanoscale library screening.
Components
  • Prothrombin
  • Thrombin light chain
KeywordsHYDROLASE / Thrombin / protease / combinatorial design of nanoscale libraries / small molecules inhibitors
Function / homology
Function and homology information


cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin ...cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / thrombin-activated receptor signaling pathway / negative regulation of astrocyte differentiation / regulation of blood coagulation / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / neutrophil-mediated killing of gram-negative bacterium / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / ligand-gated ion channel signaling pathway / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / regulation of cytosolic calcium ion concentration / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of proteolysis / negative regulation of cytokine production involved in inflammatory response / Peptide ligand-binding receptors / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / acute-phase response / Cell surface interactions at the vascular wall / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / lipopolysaccharide binding / positive regulation of insulin secretion / platelet activation / response to wounding / positive regulation of protein localization to nucleus / Golgi lumen / Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) / positive regulation of reactive oxygen species metabolic process / blood coagulation / antimicrobial humoral immune response mediated by antimicrobial peptide / regulation of cell shape / heparin binding / Thrombin signalling through proteinase activated receptors (PARs) / : / positive regulation of cell growth / blood microparticle / G alpha (q) signalling events / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / positive regulation of cell population proliferation / calcium ion binding / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. ...Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain / Kringle / Kringle, conserved site / Kringle superfamily / Kringle domain signature. / Kringle domain profile. / Kringle domain / Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain / Gamma-carboxyglutamic acid-rich (GLA) domain superfamily / Vitamin K-dependent carboxylation domain. / Gla domain profile. / Domain containing Gla (gamma-carboxyglutamate) residues. / Kringle-like fold / 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 / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsChinellato, M. / Zsolt, B. / Angelini, A. / Heinis, C. / Cendron, L.
Funding support Italy, 1items
OrganizationGrant numberCountry
Italian Ministry of Education Italy
CitationJournal: To Be Published
Title: Small molecule ligand development by nanoscale library synthesis and functional screening of crude product
Authors: Zsolt, B. / Deng, X. / Zarda, A. / Menoud, G. / Will, E. / Nielsen, A.R. / Farrera-Soler, L. / Chinellato, M. / Cendron, L. / Angelini, A. / Heinis, C.
History
DepositionOct 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 5, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Thrombin light chain
B: Prothrombin
C: Thrombin light chain
D: Prothrombin
E: Thrombin light chain
F: Prothrombin
G: Thrombin light chain
H: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)144,60018
Polymers141,6868
Non-polymers2,91510
Water57632
1
A: Thrombin light chain
B: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2115
Polymers35,4212
Non-polymers7903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2530 Å2
ΔGint-18 kcal/mol
Surface area13080 Å2
MethodPISA
2
C: Thrombin light chain
D: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,1884
Polymers35,4212
Non-polymers7672
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2530 Å2
ΔGint-6 kcal/mol
Surface area12740 Å2
MethodPISA
3
E: Thrombin light chain
F: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,2115
Polymers35,4212
Non-polymers7903
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2460 Å2
ΔGint-19 kcal/mol
Surface area13220 Å2
MethodPISA
4
G: Thrombin light chain
H: Prothrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9904
Polymers35,4212
Non-polymers5682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2370 Å2
ΔGint-22 kcal/mol
Surface area12350 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.700, 85.325, 214.280
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein/peptide / Protein / Sugars , 3 types, 11 molecules ACEGBDFH

#1: Protein/peptide
Thrombin light chain


Mass: 5641.175 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: missing residues are not visible in the electron density maps
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734
#2: Protein
Prothrombin / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Details: missing residues are not visible in the electron density maps
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Homo sapiens (human) / References: UniProt: P00734, thrombin
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 3 / Source method: obtained synthetically / 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

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Non-polymers , 3 types, 39 molecules

#3: Chemical
ChemComp-A1ITQ / ~{N}-[(3~{S})-4-[3-(2-azanyl-2-oxidanylidene-ethyl)sulfanylpropylamino]-3-[2-(3-chlorophenyl)ethanoylamino]-4-oxidanylidene-butyl]-5-chloranyl-thiophene-2-carboxamide


Mass: 545.502 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C22H26Cl2N4O4S2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.44 Å3/Da / Density % sol: 49.63 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 100 mM Tris, 200 mM Lithium chloride pH 8.0 and 20 % w/v PEG 6000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID30B / Wavelength: 0.8371 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: May 13, 2024
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8371 Å / Relative weight: 1
ReflectionResolution: 3→44.37 Å / Num. obs: 28579 / % possible obs: 99.9 % / Redundancy: 5.5 % / CC1/2: 0.979 / Net I/σ(I): 5.7
Reflection shellResolution: 3→3.18 Å / Rmerge(I) obs: 1.49 / Mean I/σ(I) obs: 1.1 / Num. unique obs: 4520 / CC1/2: 0.541

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3→44.37 Å / SU ML: 0.47 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.24 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2662 1409 5.04 %
Rwork0.2043 --
obs0.2074 27935 97.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→44.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9215 0 181 32 9428
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049619
X-RAY DIFFRACTIONf_angle_d0.80912968
X-RAY DIFFRACTIONf_dihedral_angle_d7.5781317
X-RAY DIFFRACTIONf_chiral_restr0.0491341
X-RAY DIFFRACTIONf_plane_restr0.0151663
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.110.41161340.33122623X-RAY DIFFRACTION99
3.11-3.230.36151350.29972648X-RAY DIFFRACTION99
3.23-3.380.32471450.26972631X-RAY DIFFRACTION99
3.38-3.560.30281380.23892662X-RAY DIFFRACTION98
3.56-3.780.31481410.2342613X-RAY DIFFRACTION98
3.78-4.070.26721530.19892604X-RAY DIFFRACTION97
4.07-4.480.24951320.1662643X-RAY DIFFRACTION98
4.48-5.130.21211260.16042678X-RAY DIFFRACTION98
5.13-6.460.24881460.19532673X-RAY DIFFRACTION97
6.46-44.370.21591590.17532751X-RAY DIFFRACTION95

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