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- PDB-5gds: HIRUNORMS ARE TRUE HIRUDIN MIMETICS. THE CRYSTAL STRUCTURE OF HUM... -

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Basic information

Entry
Database: PDB / ID: 5gds
TitleHIRUNORMS ARE TRUE HIRUDIN MIMETICS. THE CRYSTAL STRUCTURE OF HUMAN ALPHA-THROMBIN:HIRUNORM V COMPLEX
Components
  • (ALPHA-THROMBIN) x 2
  • HIRUNORM V
KeywordsHYDROLASE/HYDROLASE INHIBITOR / SERINE PROTEASE-INHIBITOR complex / THROMBIN / THROMBIN SYNTHETIC INHIBITORS / ANTITHROMBOTICS / HIRUNORMS / HIRUDIN-LIKE BINDING MODE / 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 / 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 / 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 / THE STRUCTURE WAS ANALYZED BY DIFFERENCE FOURIER TECHNIQUES / Resolution: 2.1 Å
AuthorsDe Simone, G. / Lombardi, A. / Galdiero, S. / Nastri, F. / Della Morte, R. / Staiano, N. / Pedone, C. / Bolognesi, M. / Pavone, V.
Citation
Journal: Protein Sci. / Year: 1998
Title: Hirunorms are true hirudin mimetics. The crystal structure of human alpha-thrombin-hirunorm V complex.
Authors: De Simone, G. / Lombardi, A. / Galdiero, S. / Nastri, F. / Della Morte, R. / Staiano, N. / Pedone, C. / Bolognesi, M. / Pavone, V.
#1: Journal: J.Med.Chem. / Year: 1996
Title: Rational Design of True Hirudin Mimetics: Synthesis and Characterization of Multisite-Directed Alpha-Thrombin Inhibitors
Authors: Lombardi, A. / Nastri, F. / Della Morte, R. / Rossi, A. / De Rosa, A. / Staiano, N. / Pedone, C. / Pavone, V.
#2: Journal: J.Mol.Biol. / Year: 1991
Title: Refined Structure of the Hirudin-Thrombin Complex
Authors: Rydel, T.J. / Tulinsky, A. / Bode, W. / Huber, R.
History
DepositionJul 17, 1997Processing site: BNL
Revision 1.0Jan 21, 1998Provider: repository / Type: Initial release
Revision 1.1Mar 21, 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 1.3Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / database_PDB_caveat ...chem_comp / database_PDB_caveat / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_ptnr2_PDB_ins_code / _struct_conn.pdbx_role / _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
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Aug 9, 2023Group: Advisory / Database references ...Advisory / Database references / Refinement description / Structure summary
Category: chem_comp / database_2 ...chem_comp / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: ALPHA-THROMBIN
H: ALPHA-THROMBIN
I: HIRUNORM V
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,0564
Polymers36,8353
Non-polymers2211
Water2,396133
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5780 Å2
ΔGint-4 kcal/mol
Surface area13150 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.900, 72.800, 73.300
Angle α, β, γ (deg.)90.00, 100.70, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide ALPHA-THROMBIN


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


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


Mass: 2958.211 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 133 / Source method: isolated from a natural source / Formula: H2O
Compound detailsTHROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN INDICATOR *L* IS USED FOR RESIDUES 1H - 15 ...THROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN INDICATOR *L* IS USED FOR RESIDUES 1H - 15 AND CHAIN INDICATOR *H* IS USED FOR RESIDUES 16 - 247. CHAIN INDICATOR *I* IS USED FOR HIRUNORM V INHIBITOR.
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).

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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: 2.4 Å3/Da / Density % sol: 49 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7
Details: THE CRYSTALS OF THROMBIN:HIRUNORM V COMPLEX WERE GROWN, AS DESCRIBED BY SKRZYPEZAK ET AL. (1991) J. MOL. BIOL.,221,1379-1393 BY VAPOR DIFFUSION METHODS AT 4 C. A 6 MICROLITER DROP, ...Details: THE CRYSTALS OF THROMBIN:HIRUNORM V COMPLEX WERE GROWN, AS DESCRIBED BY SKRZYPEZAK ET AL. (1991) J. MOL. BIOL.,221,1379-1393 BY VAPOR DIFFUSION METHODS AT 4 C. A 6 MICROLITER DROP, CONTAINING 0.05 M SODIUM HEPES (PH 7.0) 10% (W/V) PEG 4000 0.02% NAN3, 20 MG/ML. THROMBIN:HIRUNORM V COMPLEX WAS EQUILIBRATED AGAINST A PRECIPITATING SOLUTION CONTAINING 0.1 M SODIUM HEPES (PH 7.0) 20% (W/V) PEG 4000 0.04% NAN3. CRYSTAL OF THROMBIN:HIRUGEN COMPLEX WERE CRUSHED AND INDIVIDUAL SEEDS WERE USED FOR CROSS-SEEDING EXPERIMENTS., vapor diffusion, temperature 277K
Crystal grow
*PLUS
Temperature: 4 ℃ / Method: vapor diffusion
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDChemical formula
10.05 Msodium Hepes1drop
210 %(w/v)PEG40001drop
30.02 %1dropNaN3
412 mg/mlthrombin-hirugen complex1drop
50.1 Msodium Hepes1reservoir
620 %(w/v)PEG40001reservoir
70.04 %1reservoirNaN3

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Data collection

DiffractionMean temperature: 293 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jan 10, 1996 / Details: COLLIMATOR
RadiationMonochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.1→20 Å / Num. obs: 21615 / % possible obs: 99.4 % / Redundancy: 2.5 % / Biso Wilson estimate: 28.7 Å2 / Rmerge(I) obs: 0.072 / Net I/σ(I): 5.8
Reflection shellResolution: 2.1→2.17 Å / Redundancy: 2.5 % / Rmerge(I) obs: 0.38 / Mean I/σ(I) obs: 2 / % possible all: 98.7
Reflection
*PLUS
Num. measured all: 54776
Reflection shell
*PLUS
% possible obs: 98.7 %

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Processing

Software
NameVersionClassification
MOSFLMdata reduction
CCP4data reduction
CCP4model building
TNT5Erefinement
CCP4data scaling
CCP4phasing
RefinementMethod to determine structure: THE STRUCTURE WAS ANALYZED BY DIFFERENCE FOURIER TECHNIQUES
Starting model: PDB ENTRY 1HAH (J. VIJAYALAKSHMI ET AL., 1994, PROTEIN SCI. 3,2254-71)

1hah


Resolution: 2.1→20 Å / σ(F): 0
Details: THE REGIONS WITH INTERRUPTED ELECTRON DENSITIES ARE FOUND IN THE N-TERMINAL AND C-TERMINAL REGIONS OF CHAIN L, THE C-TERMINAL REGION OF CHAIN H, AND SOME RESIDUES IN THE AUTOLYSIS LOOP. ...Details: THE REGIONS WITH INTERRUPTED ELECTRON DENSITIES ARE FOUND IN THE N-TERMINAL AND C-TERMINAL REGIONS OF CHAIN L, THE C-TERMINAL REGION OF CHAIN H, AND SOME RESIDUES IN THE AUTOLYSIS LOOP. THESE REGIONS INCLUDE: THR L 1H - GLU L 1C; ASP L 14L - ARG L 15; THR H 147 AND TRP H 148; GLY H 246 AND GLU H 247. RESIDUES THR H 149 - LYS H 149E IN THE GAMMA AUTOLYSIS LOOP ARE FOUND WITH NO ELECTRON DENSITIES AND ARE NOT INCLUDED IN THIS ENTRY. THERE IS NO ELECTRON DENSITY FOT HIRUNORM V RESIDUES I 5 - I 15. OTHER ATOMS WITH NO DENSITY ARE GIVEN OCCUPANCY VALUES OF 0.00 IN THIS ENTRY.
RfactorNum. reflection% reflection
Rwork0.176 --
all-21609 -
obs-21609 97 %
Solvent computationBsol: 158.7 Å2 / ksol: 0.834 e/Å3
Refinement stepCycle: LAST / Resolution: 2.1→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2476 0 14 133 2623
Refine LS restraints
Refine-IDTypeDev idealNumberWeight
X-RAY DIFFRACTIONt_bond_d0.018348318
X-RAY DIFFRACTIONt_angle_deg2.8347440
X-RAY DIFFRACTIONt_dihedral_angle_d17.83515037
X-RAY DIFFRACTIONt_incorr_chiral_ct0
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes0.0216229
X-RAY DIFFRACTIONt_gen_planes0.02136299
X-RAY DIFFRACTIONt_it
X-RAY DIFFRACTIONt_nbd0.238125
Software
*PLUS
Name: TNT / Version: 5E / Classification: refinement
Refinement
*PLUS
Num. reflection obs: 21615 / Rfactor obs: 0.176
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev idealWeight
X-RAY DIFFRACTIONt_dihedral_angle_d
X-RAY DIFFRACTIONt_dihedral_angle_deg17.8357
X-RAY DIFFRACTIONt_plane_restr0.02199

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