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- PDB-1e0f: Crystal structure of the human alpha-thrombin-haemadin complex: a... -

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Basic information

Entry
Database: PDB / ID: 1e0f
TitleCrystal structure of the human alpha-thrombin-haemadin complex: an exosite II-binding inhibitor
Components
  • (THROMBIN) x 2
  • HAEMADIN
KeywordsHYDROLASE / COAGULATION/CRYSTAL STRUCTURE/HEPARIN-B / COAGULATION/CRYSTAL STRUCTURE/HEPARIN-BINDING SITE/ HIRUDIN/THROMBIN INHIBITOR
Function / homology
Function and homology information


positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / 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 / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / 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 / acute-phase response / Regulation of Complement cascade / 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 / antimicrobial humoral immune response mediated by antimicrobial peptide / 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 / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / blood microparticle / 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
Haemadin / Haemadin / Thrombin Inhibitor (Hirudin); Chain I / Thrombin Inhibitor (Hirudin), subunit I / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain ...Haemadin / Haemadin / Thrombin Inhibitor (Hirudin); Chain I / Thrombin Inhibitor (Hirudin), subunit I / Proteinase inhibitor I14, 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 / Distorted Sandwich / 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 domain profile. / Serine proteases, trypsin family, serine active site. / 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
Prothrombin / Thrombininhibitor
Similarity search - Component
Biological speciesHAEMADIPSA SYLVESTRIS (Indian leech)
HOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsRichardson, J.L. / Kroeger, B. / Hoefken, W. / Pereira, P. / Huber, R. / Bode, W. / Fuentes-Prior, P.
Citation
Journal: Embo J. / Year: 2000
Title: Crystal Structure of the Human Alpha-Thrombin-Haemadin Complex: An Exosite II-Binding Inhibitor
Authors: Richardson, J.L. / Kroeger, B. / Hoeffken, W. / Sadler, J.E. / Pereira, P. / Huber, R. / Bode, W. / Fuentes-Prior, P.
#1: Journal: J.Biol.Chem. / Year: 1993
Title: Isolation, Sequence Analysis, and Cloning of Haemadin an Anticoagulant Peptide from the Indian Leech
Authors: Strube, K.-H. / Kroeger, B. / Bialojan, S. / Otte, M. / Dodt, J.
#2: Journal: Protein Sci. / Year: 1992
Title: The Refined 1.9 Angstrom X-Ray Crystal Structure of D-Phe-Pro-Arg-Chloromethylketone Inhibited Human Alpha Thrombin: Structure Analysis, Overall Structure, Electrostatic Properties, Detailed ...Title: The Refined 1.9 Angstrom X-Ray Crystal Structure of D-Phe-Pro-Arg-Chloromethylketone Inhibited Human Alpha Thrombin: Structure Analysis, Overall Structure, Electrostatic Properties, Detailed Active Site Geometry and Structure Function Relatioships
Authors: Bode, W. / Turk, D. / Karshikov, A.
History
DepositionMar 27, 2000Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 3, 2000Provider: repository / Type: Initial release
Revision 1.1Nov 21, 2012Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Source and taxonomy / Structure summary
Revision 1.2Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.3May 8, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.method
Revision 1.4Dec 6, 2023Group: Advisory / Data collection ...Advisory / 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_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conn
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.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "B" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "B" IN EACH CHAIN ON SHEET RECORDS BELOW IS ACTUALLY AN 6-STRANDED BARREL THIS IS REPRESENTED BY A 7-STRANDED SHEET IN WHICH THE FIRST AND LAST STRANDS ARE IDENTICAL.

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: THROMBIN
B: THROMBIN
C: THROMBIN
D: THROMBIN
E: THROMBIN
F: THROMBIN
I: HAEMADIN
J: HAEMADIN
K: HAEMADIN


Theoretical massNumber of molelcules
Total (without water)120,4559
Polymers120,4559
Non-polymers00
Water1,20767
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area20200 Å2
ΔGint-71.6 kcal/mol
Surface area57980 Å2
MethodPQS
Unit cell
Length a, b, c (Å)121.670, 50.570, 129.740
Angle α, β, γ (deg.)90.00, 114.76, 90.00
Int Tables number3
Space group name H-MP121

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Components

#1: Protein/peptide THROMBIN


Mass: 4096.534 Da / Num. of mol.: 3 / Source method: isolated from a natural source
Details: HUMAN THROMBIN WAS PURIFIED FROM HUMAN SERUM ACCORDING TO REPORTED PROTOCOLS
Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00734
#2: Protein THROMBIN / FACTOR IIA


Mass: 29792.273 Da / Num. of mol.: 3 / Fragment: NO / Source method: isolated from a natural source
Details: HUMAN THROMBIN WAS PURIFIED FROM HUMAN SERUM ACCORDING TO REPORTED PROTOCOLS
Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD / References: UniProt: P00734, thrombin
#3: Protein HAEMADIN


Mass: 6262.853 Da / Num. of mol.: 3 / Fragment: NO
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HAEMADIPSA SYLVESTRIS (Indian leech)
Description: RECOMBINANTLY EXPRESSED IN E. COLI AS A MALTOSE BINDING PROTEIN CONJUGATE
Plasmid: PMAL-P2 / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): DH5[ALPHA] / References: UniProt: Q25163
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 67 / Source method: isolated from a natural source / Formula: H2O
Sequence detailsCHYMOTRYPSIN NUMBERING (RATHER THAN SEQUENTIAL) SYSTEM IS USED, BASED ON THE TOPOLOGICAL ALIGNMENT ...CHYMOTRYPSIN NUMBERING (RATHER THAN SEQUENTIAL) SYSTEM IS USED, BASED ON THE TOPOLOGICAL ALIGNMENT WITH THE STRUCTURE OF CHYMOTRYPSIN (W.BODE ET AL., 1989, EMBO J. 8, 3467-3475). IN SOLUTION C-TERMINAL PEPTIDE BINDS TO EXOSITE II

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 2

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Sample preparation

CrystalDensity Matthews: 3.08 Å3/Da / Density % sol: 60 %
Crystal growMethod: vapor diffusion, sitting drop / pH: 5.56
Details: VAPOUR-DIFFUSION SITTING DROP,0.1 M NA CITRATE PH 5.56 14% (W/V) PEG4000, 12.5% (V/V) ISOPROPANOL
Crystal grow
*PLUS
Temperature: 22 ℃ / Method: vapor diffusion
Details: drop consists of equal amounts of protein and precipitant solutions
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formulaDetails
15 mg/mlprotein1drop
210 mMTris-HCl1drop
320 mM1dropNaCl
40.02 %(w/v)1dropNaN3
5100 mMsodium citrate1reservoirprecipitant
614 %(w/v)PEG40001reservoirprecipitant
712.5 %(v/v)isopropanol1reservoirprecipitant

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Data collection

DiffractionMean temperature: 289 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Sep 15, 1998
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.1→32.791 Å / Num. obs: 23938 / Rmerge(I) obs: 0.109
Reflection
*PLUS
% possible obs: 81.2 % / Num. measured all: 126754

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Processing

Software
NameVersionClassification
X-PLOR3.851refinement
MOSFLMdata reduction
Agrovatadata scaling
ROTAVATAdata scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HTC

4htc


Resolution: 3.1→10 Å / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.255 -5 %RANDOM
Rwork0.208 ---
obs0.208 22278 81.2 %-
Refinement stepCycle: LAST / Resolution: 3.1→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8374 0 0 67 8441
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.006
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_deg1.515
X-RAY DIFFRACTIONx_angle_deg_na
X-RAY DIFFRACTIONx_angle_deg_prot
X-RAY DIFFRACTIONx_dihedral_angle_d23.552
X-RAY DIFFRACTIONx_dihedral_angle_d_na
X-RAY DIFFRACTIONx_dihedral_angle_d_prot
X-RAY DIFFRACTIONx_improper_angle_d1.144
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: 3.851 / Classification: refinement
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_deg1.52
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg23.55
X-RAY DIFFRACTIONx_improper_angle_d
X-RAY DIFFRACTIONx_improper_angle_deg1.144

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