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- PDB-12cx: D189K thrombin inhibited with D-Phe-Pro-Phe-Chloromethylketone -

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Basic information

Entry
Database: PDB / ID: 12cx
TitleD189K thrombin inhibited with D-Phe-Pro-Phe-Chloromethylketone
Components
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsBLOOD CLOTTING / serine protease / inhibitor
Function / homology
Function and homology information


negative regulation of astrocyte differentiation / thrombospondin receptor activity / thrombin / thrombin-activated receptor signaling pathway / Defective factor XII causes hereditary angioedema / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / Platelet Aggregation (Plug Formation) / Defective F8 cleavage by thrombin ...negative regulation of astrocyte differentiation / thrombospondin receptor activity / thrombin / thrombin-activated receptor signaling pathway / Defective factor XII causes hereditary angioedema / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / Platelet Aggregation (Plug Formation) / Defective F8 cleavage by thrombin / positive regulation of collagen biosynthetic process / Fibrin formation / negative regulation of platelet activation / negative regulation of blood coagulation / negative regulation of fibrinolysis / positive regulation of blood coagulation / negative regulation of proteolysis / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / fibrinolysis / Gamma-carboxylation of protein precursors / Amplification and propagation of coagulation cascade / Removal of aminoterminal propeptides from gamma-carboxylated proteins / Initiation of coagulation cascade / regulation of cytosolic calcium ion concentration / negative regulation of cytokine production involved in inflammatory response / Regulation of clotting cascade / Regulation of Complement cascade / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of release of sequestered calcium ion into cytosol / Cell surface interactions at the vascular wall / growth factor activity / Peptide ligand-binding receptors / response to wounding / lipopolysaccharide binding / platelet activation / positive regulation of protein localization to nucleus / Golgi lumen / blood coagulation / 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 / heparin binding / Thrombin signalling through proteinase activated receptors (PARs) / Dengue Virus-Host Interactions / antimicrobial humoral immune response mediated by antimicrobial peptide / blood microparticle / extracellular matrix / G alpha (q) signalling events / cell surface receptor signaling pathway / receptor ligand activity / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / calcium ion binding / proteolysis / 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. / Serine proteases, trypsin family, serine active site. / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin domain profile. / Trypsin-like serine protease / Serine proteases, trypsin domain / Trypsin / Peptidase S1, PA clan
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.42 Å
AuthorsFriet, T. / Mohammed, B.M. / Sukumar, N. / Di Cera, E.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)HL049413, HL139554, HL147821 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)P30GM133893 United States
Department of Energy (DOE, United States)KP1607011 United States
CitationJournal: J.Thromb.Haemost. / Year: 2026
Title: Structural analysis of the primary specificity of thrombin.
Authors: Friet, T. / Mikhail, G. / Mohammed, B.M. / Pelc, L.A. / Dei Rossi, A. / Korolev, S. / Di Cera, E.
History
DepositionMar 27, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 7, 2026Provider: 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: Thrombin heavy chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,7454
Polymers37,0802
Non-polymers6652
Water3,477193
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 Å2
ΔGint-9 kcal/mol
Surface area12320 Å2
MethodPISA
Unit cell
Length a, b, c (Å)155.053, 50.208, 44.727
Angle α, β, γ (deg.)90.000, 103.928, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11A-437-

HOH

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Components

#1: Protein/peptide Thrombin light chain


Mass: 5641.175 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00734
#2: Protein Thrombin heavy chain


Mass: 31439.127 Da / Num. of mol.: 1 / Mutation: D519K
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / Production host: Mesocricetus auratus (golden hamster) / References: UniProt: P00734
#3: Chemical ChemComp-A1DFL / D-phenylalanyl-N-[(2S,3S)-4-chloro-3-hydroxy-1-phenylbutan-2-yl]-L-prolinamide


Mass: 443.966 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H30ClN3O3 / Feature type: SUBJECT OF INVESTIGATION
#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.: 1 / Source method: isolated from a natural 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
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 193 / Source method: isolated from a natural source / Formula: H2O
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: 2.33 Å3/Da / Density % sol: 47.27 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, hanging drop
Details: 0.2 M Sodium chloride, 0.1 M BIS-TRIS pH 5.5, 25% w/v Polyethylene glycol 3,350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.97934 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 4, 2025
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97934 Å / Relative weight: 1
ReflectionResolution: 1.42→47.63 Å / Num. obs: 62265 / % possible obs: 99.5 % / Redundancy: 6.8 % / Biso Wilson estimate: 11.25 Å2 / CC1/2: 0.986 / Rmerge(I) obs: 0.18 / Rpim(I) all: 0.074 / Rrim(I) all: 0.195 / Χ2: 0.93 / Net I/σ(I): 5.8 / Num. measured all: 423993
Reflection shellResolution: 1.42→1.5 Å / % possible obs: 98.2 % / Redundancy: 6.3 % / Rmerge(I) obs: 0.881 / Num. measured all: 56500 / Num. unique obs: 8912 / CC1/2: 0.432 / Rpim(I) all: 0.375 / Rrim(I) all: 0.959 / Χ2: 0.83 / Net I/σ(I) obs: 2.2

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Processing

Software
NameVersionClassification
PHENIX2.0_5936refinement
Aimlessdata scaling
XDSdata reduction
PHASERphasing
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.42→43.41 Å / SU ML: 0.1828 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 24.5005
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2474 3047 4.9 %
Rwork0.2225 59197 -
obs0.2237 62244 99.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 16.64 Å2
Refinement stepCycle: LAST / Resolution: 1.42→43.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2229 0 44 193 2466
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00572348
X-RAY DIFFRACTIONf_angle_d0.89853170
X-RAY DIFFRACTIONf_chiral_restr0.0849331
X-RAY DIFFRACTIONf_plane_restr0.0072399
X-RAY DIFFRACTIONf_dihedral_angle_d16.4804899
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.42-1.450.34321270.34112603X-RAY DIFFRACTION95.92
1.45-1.470.32011280.31132654X-RAY DIFFRACTION99.22
1.47-1.50.29531260.29642651X-RAY DIFFRACTION98.13
1.5-1.520.34231350.28572694X-RAY DIFFRACTION99.4
1.52-1.550.27381450.26892627X-RAY DIFFRACTION98.75
1.55-1.580.26641550.25682650X-RAY DIFFRACTION99.4
1.58-1.620.29491400.24922679X-RAY DIFFRACTION99.23
1.62-1.660.26631300.24242715X-RAY DIFFRACTION99.3
1.66-1.70.29861280.23632661X-RAY DIFFRACTION99.61
1.7-1.740.2611420.23122692X-RAY DIFFRACTION99.47
1.74-1.790.29111470.22292678X-RAY DIFFRACTION99.65
1.79-1.850.26051300.23442701X-RAY DIFFRACTION99.79
1.85-1.920.25661550.21812663X-RAY DIFFRACTION99.79
1.92-20.22711470.20742703X-RAY DIFFRACTION99.86
2-2.090.25091390.20742692X-RAY DIFFRACTION99.89
2.09-2.20.25341630.21592677X-RAY DIFFRACTION100
2.2-2.330.21481240.2112741X-RAY DIFFRACTION100
2.33-2.510.26161250.22462720X-RAY DIFFRACTION100
2.51-2.770.26631400.22062702X-RAY DIFFRACTION100
2.77-3.170.23831490.21552725X-RAY DIFFRACTION99.97
3.17-3.990.2041300.19742760X-RAY DIFFRACTION100
3.99-43.410.20331420.19412809X-RAY DIFFRACTION99.9

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