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- PDB-3f68: Thrombin Inhibition -

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Basic information

Entry
Database: PDB / ID: 3f68
TitleThrombin Inhibition
Components
  • (Prothrombin) x 2
  • Hirudin variant-2
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Blood Clotting / Hydrolase Inhibitor / Acute phase / Blood coagulation / Gamma-carboxyglutamic acid / Glycoprotein / Hydrolase / Kringle / Protease / Secreted / Serine protease / Protease inhibitor / Serine protease inhibitor / Sulfation / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of lipid kinase activity / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin ...positive regulation of lipid kinase activity / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / positive regulation of blood coagulation / negative regulation of fibrinolysis / Gamma-carboxylation of protein precursors / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / regulation of cytosolic calcium ion concentration / Intrinsic Pathway of Fibrin Clot Formation / Peptide ligand-binding receptors / positive regulation of release of sequestered calcium ion into cytosol / Regulation of Complement cascade / acute-phase response / negative regulation of proteolysis / Cell surface interactions at the vascular wall / lipopolysaccharide binding / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / serine-type endopeptidase inhibitor activity / 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 / Thrombin signalling through proteinase activated receptors (PARs) / heparin binding / regulation of cell shape / positive regulation of cell growth / G alpha (q) signalling events / collagen-containing extracellular matrix / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / calcium ion binding / positive regulation of cell population proliferation / proteolysis / extracellular space / extracellular exosome / extracellular region / plasma membrane
Similarity search - Function
Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain ...Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / 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 / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin family, serine active site. / Serine proteases, trypsin domain profile. / 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
N-acetyl-3-cyclohexyl-D-alanyl-N-(3-chlorobenzyl)-L-prolinamide / Chem-91U / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo Medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.75 Å
AuthorsBaum, B. / Heine, A. / Klebe, G.
CitationJournal: J.Mol.Biol. / Year: 2009
Title: Think twice: understanding the high potency of bis(phenyl)methane inhibitors of thrombin.
Authors: Baum, B. / Muley, L. / Heine, A. / Smolinski, M. / Hangauer, D. / Klebe, G.
History
DepositionNov 5, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 20, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Dec 12, 2012Group: Other
Revision 1.3Oct 26, 2016Group: Structure summary
Revision 1.4Oct 25, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Jul 24, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.name ..._software.classification / _software.name / _software.version / _struct_conn.pdbx_leaving_atom_flag
Revision 1.6Sep 6, 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 / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.ptnr2_auth_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.7Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.8Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Prothrombin
H: Prothrombin
I: Hirudin variant-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7776
Polymers35,2973
Non-polymers4803
Water1,874104
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-31 kcal/mol
Surface area12410 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.280, 71.950, 72.500
Angle α, β, γ (deg.)90.00, 100.05, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-1069-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: UNP residues 328-363, Thrombin light chain / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-2


Mass: 1420.451 Da / Num. of mol.: 1 / Fragment: UNP residues 61-71 / Source method: obtained synthetically
Details: Synthetic Fragment of Hirudin from Hirudo Medicinalis
Source: (synth.) Hirudo Medicinalis (medicinal leech) / References: UniProt: P09945

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Protein , 1 types, 1 molecules H

#2: Protein Prothrombin / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin ...Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain / Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: UNP residues 364-622, Thrombin heavy chain / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin

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Non-polymers , 3 types, 107 molecules

#4: Chemical ChemComp-91U / N-acetyl-3-cyclohexyl-D-alanyl-N-(3-chlorobenzyl)-L-prolinamide


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 433.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H32ClN3O3
References: N-acetyl-3-cyclohexyl-D-alanyl-N-(3-chlorobenzyl)-L-prolinamide
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 51.89 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: Phosphate Buffer, Sodium Chloride, PEG 8000, pH 7.5, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933 Å
DetectorType: ADSC QUANTUM 210 / Detector: CCD / Date: Oct 13, 2008
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 1.75→29.2 Å / Num. obs: 35166 / % possible obs: 98.5 % / Redundancy: 2.4 % / Rmerge(I) obs: 0.064 / Rsym value: 0.064 / Net I/σ(I): 11.7
Reflection shellResolution: 1.75→1.85 Å / Redundancy: 2.3 % / Rmerge(I) obs: 0.707 / Mean I/σ(I) obs: 1.2 / Num. unique all: 11620 / Rsym value: 0.707 / % possible all: 98.1

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Processing

Software
NameVersionClassification
SHELXL-97refinement
CNSrefinement
MAR345CCDdata collection
MOSFLMdata reduction
SCALEPACKdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1H8D

1h8d


Resolution: 1.75→10 Å / Num. parameters: 9701 / Num. restraintsaints: 9498 / Cross valid method: FREE R / σ(F): 0 / Stereochemistry target values: ENGH AND HUBER
Details: ANISOTROPIC SCALING APPLIED BY THE METHOD OF PARKIN, MOEZZI & HOPE, J.APPL.CRYST.28(1995)53-56
RfactorNum. reflection% reflectionSelection details
Rfree0.2563 1730 5 %RANDOM
Rwork0.196 ---
all0.2105 34856 --
obs0.2105 34856 97.9 %-
Refine analyzeNum. disordered residues: 0 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 2421.5
Refinement stepCycle: LAST / Resolution: 1.75→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2284 0 32 104 2420
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.007
X-RAY DIFFRACTIONs_angle_d0.025
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0282
X-RAY DIFFRACTIONs_zero_chiral_vol0.038
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.048
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.009
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.09
X-RAY DIFFRACTIONs_approx_iso_adps0

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