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- PDB-1qur: HUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED ... -

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Basic information

Entry
Database: PDB / ID: 1qur
TitleHUMAN ALPHA-THROMBIN IN COMPLEX WITH BIVALENT, BENZAMIDINE-BASED SYNTHETIC INHIBITOR
Components
  • BIVALENT INHIBITOR (BZA-2 HIRULOG)
  • HUMAN THROMBIN (ALPHA CHAIN)
  • HUMAN THROMBIN (BETA CHAIN)
KeywordsHYDROLASE/HYDROLASE INHIBITOR / TRYPSIN LIKE SERINE PROTEASE / BLOOD COAGULATION / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


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 ...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 / regulation of cytosolic calcium ion concentration / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / 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 / 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) / 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
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. / 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
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / Resolution: 2 Å
AuthorsRenatus, M. / Steinmetzer, T.
CitationJournal: Eur.J.Biochem. / Year: 1999
Title: Design and evaluation of novel bivalent thrombin inhibitors based on amidinophenylalanines.
Authors: Steinmetzer, T. / Renatus, M. / Kunzel, S. / Eichinger, A. / Bode, W. / Wikstrom, P. / Hauptmann, J. / Sturzebecher, J.
History
DepositionJul 2, 1999Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 1999Provider: repository / Type: Initial release
Revision 1.1Apr 27, 2008Group: 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 2.0Nov 15, 2023Group: Advisory / Atomic model ...Advisory / Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_validate_polymer_linkage / struct_conn / struct_ref_seq
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_ref_seq.db_align_beg / _struct_ref_seq.db_align_end
Revision 2.1Oct 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: HUMAN THROMBIN (ALPHA CHAIN)
H: HUMAN THROMBIN (BETA CHAIN)
I: BIVALENT INHIBITOR (BZA-2 HIRULOG)


Theoretical massNumber of molelcules
Total (without water)35,1873
Polymers35,1873
Non-polymers00
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5570 Å2
ΔGint-5 kcal/mol
Surface area13690 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.320, 72.410, 72.330
Angle α, β, γ (deg.)90.00, 100.27, 90.00
Int Tables number5
Space group name H-MC121
DetailsThe biological assembly of alpha-thrombin consists of the large and small subunit, linked by a disulfid bridge

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Components

#1: Protein/peptide HUMAN THROMBIN (ALPHA CHAIN)


Mass: 3188.627 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734
#2: Protein HUMAN THROMBIN (BETA CHAIN)


Mass: 29594.055 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734
#3: Protein/peptide BIVALENT INHIBITOR (BZA-2 HIRULOG)


Mass: 2404.564 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: The inhibitor was chemically synthesized AS COMBINATION OF ORGANIC AND SOLID PHASE PEPTIDE SYNTHESIS. THE ACTIVE SITE BINDING PORTION IS DERIVED FROM THE SYNTHETICAL INHIBITOR NAPAP,THE ...Details: The inhibitor was chemically synthesized AS COMBINATION OF ORGANIC AND SOLID PHASE PEPTIDE SYNTHESIS. THE ACTIVE SITE BINDING PORTION IS DERIVED FROM THE SYNTHETICAL INHIBITOR NAPAP,THE SEQUENCE OF THE EXOSITE BINDING PORTION WAS DERIVED FROM THE NATURALLY OCCURING INHIBITOR HIRUDIN, ISOLATED FROM THE MEDICAL LEECH AND THE SYNTHETICALLY SYNTHESIZED EXOSITE INHIBITOR MDL-28,050.
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O
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: 2.65 Å3/Da / Density % sol: 53.65 %
Crystal growTemperature: 280 K / Method: macro seeding
Details: 100 mM Tris/HCl, 300-500 mM NaCl, 22-32% (w/v) PEG 8000, macro seeding, temperature 280K
Crystal grow
*PLUS
Temperature: 6 ℃ / pH: 6 / Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
13 mMHEPES1drop
2150 mM1dropNaCl
422-32 %(w/v)PEG80001reservoir
5300-500 mM1reservoirNaCl
6100 mMTris-HCl1reservoir
3inhibitor1drop20 fold excess ob BZA-2

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Data collection

DiffractionMean temperature: 290 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Nov 23, 1998
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.98→9 Å / Num. all: 54304 / Num. obs: 23412 / % possible obs: 93.4 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Redundancy: 2.3 % / Biso Wilson estimate: 21.604 Å2 / Rmerge(I) obs: 0.128 / Net I/σ(I): 4
Reflection shellResolution: 1.98→2.09 Å / Redundancy: 2 % / Rmerge(I) obs: 0.476 / Mean I/σ(I) obs: 1.2 / % possible all: 82
Reflection shell
*PLUS
% possible obs: 82 %

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
SCALAdata scaling
CNSrefinement
CCP4(SCALA)data scaling
RefinementResolution: 2→9 Å / Data cutoff high rms absF: 10000 / σ(F): 0 / σ(I): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.246 23360 5 %RANDOM
Rwork0.209 ---
all-24276 --
obs-23360 96.2 %-
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--0.427 Å20 Å20.764 Å2
2--5.839 Å20 Å2
3----5.412 Å2
Refinement stepCycle: LAST / Resolution: 2→9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2472 0 0 150 2622
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONx_bond_d0.009314
X-RAY DIFFRACTIONx_angle_deg1.5248
X-RAY DIFFRACTIONx_mcbond_it1.4571.5
X-RAY DIFFRACTIONx_mcangle_it2.0862
X-RAY DIFFRACTIONx_scbond_it2.312
X-RAY DIFFRACTIONx_scangle_it3.0822.5
LS refinement shellResolution: 2→2.03 Å / Total num. of bins used: 22 /
RfactorNum. reflection
Rfree0.323 -
Rwork-53
Xplor fileSerial no: 1 / Param file: CNS_TOPPAR:protein_rep.param / Topol file: CNS_TOPPAR:water_rep.param
Software
*PLUS
Name: CNS / Classification: refinement
Refinement
*PLUS
Highest resolution: 2 Å / Lowest resolution: 9 Å / σ(F): 0 / % reflection Rfree: 5 % / Rfactor obs: 0.2085 / Rfactor Rfree: 0.2468
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal target
X-RAY DIFFRACTIONc_bond_d
X-RAY DIFFRACTIONc_angle_deg
X-RAY DIFFRACTIONc_mcbond_it1.5
X-RAY DIFFRACTIONc_scbond_it2
X-RAY DIFFRACTIONc_mcangle_it2
X-RAY DIFFRACTIONc_scangle_it2.5
LS refinement shell
*PLUS
Rfactor Rfree: 0.323

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