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- PDB-3dux: Understanding Thrombin Inhibition -

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Basic information

Entry
Database: PDB / ID: 3dux
TitleUnderstanding Thrombin Inhibition
Components
  • Hirudin variant-1
  • Thrombin Heavy Chain
  • Thrombin Light Chain
KeywordsHydrolase/Hydrolase Inhibitor / Blood Clotting / Hydrolase Inhibitor / Acute phase / Blood coagulation / Gamma-carboxyglutamic acid / Glycoprotein / Hydrolase / Kringle / Protease / Secreted / Serine protease / Hydrolase-Hydrolase Inhibitor Complex
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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
3-cyclohexyl-D-alanyl-N-(3-chlorobenzyl)-L-prolinamide / Chem-64U / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 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
DepositionJul 18, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 23, 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 1.3May 25, 2016Group: Source and taxonomy
Revision 1.4Oct 25, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Nov 1, 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 / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.7Oct 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: Thrombin Light Chain
H: Thrombin Heavy Chain
I: Hirudin variant-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7356
Polymers35,2973
Non-polymers4383
Water2,828157
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3480 Å2
ΔGint-33 kcal/mol
Surface area12140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.02, 71.44, 72.79
Angle α, β, γ (deg.)90.00, 100.50, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-1023-

HOH

21H-1109-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Thrombin Light Chain / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: blood plasma / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-1 / Lepirudin


Mass: 1420.451 Da / Num. of mol.: 1 / Fragment: Residues 54-64 / Source method: obtained synthetically
Details: Synthetic Fragment of Hirudin from Hirudo Medicinalis
Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P01050

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Protein , 1 types, 1 molecules H

#2: Protein Thrombin Heavy Chain / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: blood plasma / References: UniProt: P00734, thrombin

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Non-polymers , 3 types, 160 molecules

#4: Chemical ChemComp-64U / 3-cyclohexyl-D-alanyl-N-(3-chlorobenzyl)-L-prolinamide / (2S)-1-((2R)-2-amino-3-cyclohexyl-propanoyl)-N-((3-chlorophenyl)methyl)pyrrolidine-2-carboxamide


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 391.935 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H30ClN3O2
References: 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.: 157 / 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: 2.54 Å3/Da / Density % sol: 51.49 %
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: BESSY / Beamline: 14.2 / Wavelength: 0.91841 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: May 30, 2008
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91841 Å / Relative weight: 1
ReflectionResolution: 1.6→30 Å / Num. all: 43781 / Num. obs: 43781 / % possible obs: 94 % / Redundancy: 2.5 % / Rsym value: 0.043 / Net I/σ(I): 22.4
Reflection shellResolution: 1.6→1.63 Å / Redundancy: 2.4 % / Mean I/σ(I) obs: 2.26 / Num. unique all: 2281 / Rsym value: 0.452 / % possible all: 98.2

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Processing

Software
NameVersionClassification
SHELXmodel building
SHELXL-97refinement
MAR345CCDdata collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1H8D

1h8d


Resolution: 1.6→10 Å / Num. parameters: 9833 / Num. restraintsaints: 9480 / Cross valid method: FREE R / σ(F): 0 / σ(I): 0 / Stereochemistry target values: ENGH & HUBER
Details: ANISOTROPIC SCALING APPLIED BY THE METHOD OF PARKIN, MOEZZI & HOPE, J.APPL.CRYST.28(1995)53-56
RfactorNum. reflection% reflectionSelection details
Rfree0.247 2086 5 %RANDOM
Rwork0.2012 ---
all0.2073 41316 --
obs0.2073 41316 89.1 %-
Refine analyzeNum. disordered residues: 2 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 2444
Refinement stepCycle: LAST / Resolution: 1.6→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2258 0 29 157 2444
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.009
X-RAY DIFFRACTIONs_angle_d0.026
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0272
X-RAY DIFFRACTIONs_zero_chiral_vol0.045
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.057
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.01
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.077
X-RAY DIFFRACTIONs_approx_iso_adps0

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