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- PDB-3dhk: Bisphenylic Thrombin Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3dhk
TitleBisphenylic Thrombin Inhibitors
Components
  • Hirudin variant-1
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsBlood Clotting/Hydrolase Inhibitor / Acute phase / Blood coagulation / Cleavage on pair of basic residues / Disease mutation / Gamma-carboxyglutamic acid / Glycoprotein / Hydrolase / Kringle / Protease / Secreted / Serine protease / Zymogen / Blood Clotting-Hydrolase Inhibitor complex
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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 / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / regulation of cytosolic calcium ion concentration / 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 / 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 / regulation of cell shape / heparin binding / : / Thrombin signalling through proteinase activated receptors (PARs) / toxin activity / 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
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 / 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 / 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
Chem-23U / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.73 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
DepositionJun 18, 2008Deposition site: RCSB / Processing site: PDBJ
Revision 1.0May 19, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Sep 18, 2013Group: Derived calculations
Revision 1.3Oct 25, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.4Nov 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 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2
Revision 1.6Oct 16, 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)35,8056
Polymers35,2973
Non-polymers5083
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3450 Å2
ΔGint-31 kcal/mol
Surface area12210 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.95, 71.34, 72.44
Angle α, β, γ (deg.)90.00, 100.32, 90.00
Int Tables number5
Space group name H-MC121

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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
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, 129 molecules

#4: Chemical ChemComp-23U / beta-phenyl-D-phenylalanyl-N-(3-chlorobenzyl)-L-prolinamide


Mass: 461.983 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H28ClN3O2
#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.: 126 / 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: 2.52 Å3/Da / Density % sol: 51.17 %
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: 1.73→30 Å / Num. all: 33387 / Num. obs: 33387 / % possible obs: 91.2 % / Redundancy: 2 % / Rsym value: 0.049 / Net I/σ(I): 14.34
Reflection shellResolution: 1.73→1.76 Å / Redundancy: 1.9 % / Mean I/σ(I) obs: 2.31 / Num. unique all: 1684 / Rsym value: 0.388 / % possible all: 92.1

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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: 1.73→10 Å / Num. parameters: 9857 / Num. restraintsaints: 9618 / Cross valid method: FREE R / σ(F): 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
Rfree0.2487 1592 5 %RANDOM
Rwork0.1911 ---
all0.1967 31778 --
obs0.1967 31778 87.3 %-
Refine analyzeNum. disordered residues: 3 / Occupancy sum hydrogen: 0 / Occupancy sum non hydrogen: 2447
Refinement stepCycle: LAST / Resolution: 1.73→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2285 0 35 126 2446
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.007
X-RAY DIFFRACTIONs_angle_d0.023
X-RAY DIFFRACTIONs_similar_dist0
X-RAY DIFFRACTIONs_from_restr_planes0.0269
X-RAY DIFFRACTIONs_zero_chiral_vol0.039
X-RAY DIFFRACTIONs_non_zero_chiral_vol0.051
X-RAY DIFFRACTIONs_anti_bump_dis_restr0.011
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt0
X-RAY DIFFRACTIONs_similar_adp_cmpnt0.076
X-RAY DIFFRACTIONs_approx_iso_adps0

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