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- PDB-1qhr: NOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS -

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Basic information

Entry
Database: PDB / ID: 1qhr
TitleNOVEL COVALENT ACTIVE SITE THROMBIN INHIBITORS
Components
  • (ALPHA THROMBIN) x 2
  • HIRUGEN
KeywordsBLOOD CLOTTING/HYDROLASE INHIBITOR / PROTEINASE / BLOOD COAGULATION / TRYPSIN LIKE PROTEINASE / COMPLEX (SERINE PROTEASE-INHIBITOR) / 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
6-(2-HYDROXY-CYCLOPENTYL)-7-OXO-HEPTANAMIDINE / Prothrombin / Hirudin variant-1 / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / OTHER / Resolution: 2.2 Å
AuthorsJhoti, H. / Cleasby, A. / Reid, S. / Thomas, P. / Wonacott, A.
CitationJournal: Biochemistry / Year: 1999
Title: Crystal structures of thrombin complexed to a novel series of synthetic inhibitors containing a 5,5-trans-lactone template.
Authors: Jhoti, H. / Cleasby, A. / Reid, S. / Thomas, P.J. / Weir, M. / Wonacott, A.
History
DepositionMay 26, 1999Deposition site: PDBE / Processing site: RCSB
Revision 1.0May 31, 2000Provider: repository / Type: Initial release
Revision 1.1Oct 16, 2007Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Oct 4, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.name / _software.version
Revision 1.4Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.5Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / 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_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.6Oct 30, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: ALPHA THROMBIN
B: ALPHA THROMBIN
I: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4664
Polymers35,2403
Non-polymers2261
Water3,693205
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.700, 72.000, 73.000
Angle α, β, γ (deg.)90.00, 101.00, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide ALPHA THROMBIN / E.C.3.4.21.5


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin
#2: Protein ALPHA THROMBIN / E.C.3.4.21.5


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUGEN


Mass: 1363.399 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: THIS PEPTIDE WAS CHEMICALLY SYNTHESIZED. THE SEQUENCE FOR THIS PEPTIDE OCCURS NATURALLY IN MEDICINAL LEECH (HIRUDO MEDICINALIS).
Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28501, UniProt: P01050*PLUS
#4: Chemical ChemComp-157 / 6-(2-HYDROXY-CYCLOPENTYL)-7-OXO-HEPTANAMIDINE / GR157368


Mass: 226.315 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H22N2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 205 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY
Nonpolymer detailsGR15: ACTIVE SITE DIRECTED, ACYLATING INHIBITOR OF THROMBIN.

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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: 2.62 Å3/Da / Density % sol: 53.11 %
Crystal growpH: 7
Details: CRYSTALS WERE GROWN BY MACROSEEDING A SOLUTION OF 100MM HEPES PH 7.0, 22% PEG4K, 200MM NACL. PROTEIN CONCENTRATION OF 5MG/ML.
Crystal grow
*PLUS
pH: 7.3 / Method: vapor diffusion, hanging drop / Details: Skrzypczak, J., (1991) J. Mol. Biol., 221, 1379.
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
13.0-3.7 mg/mlprotein1drop
20.05 Msodium phosphate1drop
30.375 M1dropNaCl
40.5 mM1dropNaN3
50.1 Msodium phosphate1reservoir
61-2 mM1reservoirNaN3
725-30 %(w/v)PEG80001reservoir

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Data collection

DiffractionMean temperature: 290 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS / Wavelength: 1.5418
DetectorType: ENRAF-NONIUS / Detector: AREA DETECTOR / Details: MONOCHROMATOR
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→30 Å / Num. obs: 21972 / % possible obs: 98 % / Redundancy: 2.2 % / Rsym value: 0.06
Reflection
*PLUS
Rmerge(I) obs: 0.058

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Processing

Software
NameVersionClassification
MADNESSdata collection
CCP4data reduction
X-PLORmodel building
Quantamodel building
X-PLOR3.1refinement
MADNESSdata reduction
CCP4data scaling
X-PLORphasing
RefinementMethod to determine structure: OTHER / Resolution: 2.2→15 Å / σ(F): 2 /
RfactorNum. reflection
Rwork0.204 -
obs0.204 21972
Refinement stepCycle: LAST / Resolution: 2.2→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2475 0 16 205 2696
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.016
X-RAY DIFFRACTIONx_bond_d_na
X-RAY DIFFRACTIONx_bond_d_prot
X-RAY DIFFRACTIONx_angle_d
X-RAY DIFFRACTIONx_angle_d_na
X-RAY DIFFRACTIONx_angle_d_prot
X-RAY DIFFRACTIONx_angle_deg3.1
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_d_na
X-RAY DIFFRACTIONx_improper_angle_d_prot
X-RAY DIFFRACTIONx_mcbond_it
X-RAY DIFFRACTIONx_mcangle_it
X-RAY DIFFRACTIONx_scbond_it
X-RAY DIFFRACTIONx_scangle_it
Software
*PLUS
Name: X-PLOR / Version: 3.1 / Classification: refinement
Refinement
*PLUS
Highest resolution: 2.2 Å / Lowest resolution: 15 Å / σ(F): 2
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Type: x_angle_deg / Dev ideal: 3.1

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