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- PDB-1a46: THROMBIN COMPLEXED WITH HIRUGEN AND A BETA-STRAND MIMETIC INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 1a46
TitleTHROMBIN COMPLEXED WITH HIRUGEN AND A BETA-STRAND MIMETIC INHIBITOR
Components
  • (ALPHA-THROMBIN ...) x 2
  • HIRUGEN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COMPLEX (SERINE PROTEASE-INHIBITOR) / 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 / 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) / : / 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
MOL-106 / Chem-00K / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / PREVIOUS STRUCTURE / Resolution: 2.12 Å
AuthorsSt Charles, R. / Matthews, J.H. / Zhang, E. / Tulinsky, A. / Kahn, M.
Citation
Journal: J.Med.Chem. / Year: 1999
Title: Bound structures of novel P3-P1' beta-strand mimetic inhibitors of thrombin.
Authors: St Charles, R. / Matthews, J.H. / Zhang, E. / Tulinsky, A.
#1: Journal: Biophys.J. / Year: 1996
Title: Crystal Structures of Thrombin with Thiazole-Containing Inhibitors: Probes of the S1' Binding Site
Authors: Matthews, J.H. / Krishnan, R. / Costanzo, M.J. / Maryanoff, B.E. / Tulinsky, A.
#2: Journal: Protein Eng. / Year: 1993
Title: The Structure of a Designed Peptidomimetic Inhibitor Complex of Alpha-Thrombin
Authors: Wu, T.P. / Yee, V. / Tulinsky, A. / Chrusciel, R.A. / Nakanishi, H. / Shen, R. / Priebe, C. / Kahn, M.
#3: Journal: Blood Coagulation Fibrinolysis / Year: 1993
Title: Active Site and Exosite Binding of Alpha-Thrombin
Authors: Tulinsky, A. / Qiu, X.
History
DepositionFeb 11, 1998Processing site: BNL
Revision 1.0May 27, 1998Provider: repository / Type: Initial release
Revision 1.1Mar 24, 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 1.3Dec 12, 2012Group: Other
Revision 1.4Aug 2, 2023Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description
Category: database_2 / pdbx_database_status ...database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.process_site / _pdbx_struct_conn_angle.ptnr1_PDB_ins_code / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr1_symmetry / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_PDB_ins_code / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.ptnr3_symmetry / _pdbx_struct_conn_angle.value / _struct_conn.conn_type_id / _struct_conn.id / _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.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.ptnr1_symmetry / _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_conn.ptnr2_symmetry / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 13, 2024Group: Data collection / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / pdbx_entry_details / pdbx_modification_feature
Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: ALPHA-THROMBIN (SMALL SUBUNIT)
H: ALPHA-THROMBIN (LARGE SUBUNIT)
I: HIRUGEN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,9866
Polymers35,4113
Non-polymers5753
Water2,972165
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.300, 73.090, 73.820
Angle α, β, γ (deg.)90.00, 101.12, 90.00
Int Tables number5
Space group name H-MC121

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Components

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ALPHA-THROMBIN ... , 2 types, 2 molecules LH

#1: Protein/peptide ALPHA-THROMBIN (SMALL SUBUNIT)


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


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

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Protein/peptide , 1 types, 1 molecules I

#3: Protein/peptide HIRUGEN


Mass: 1534.554 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Hirudo medicinalis (medicinal leech) / References: UniProt: P09945

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Non-polymers , 3 types, 168 molecules

#4: Chemical ChemComp-NA / SODIUM ION / MOL 106


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-00K / (1S,7S)-7-amino-N-[(2R,3S)-7-amino-1-(cyclohexylamino)-2-hydroxy-1-oxoheptan-3-yl]-7-benzyl-8-oxohexahydro-1H-pyrazolo[1,2-a]pyridazine-1-carboxamide / MOL-106


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 528.687 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H44N6O4 / References: MOL-106
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsTHROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1H - 15 ...THROMBIN IS CLEAVED BETWEEN RESIDUES 15 AND 16. CHAIN IDENTIFIER *L* IS USED FOR RESIDUES 1H - 15 AND CHAIN IDENTIFIER *H* IS USED FOR RESIDUES 16 - 247. CHAIN IDENTIFIER *I* IS USED FOR HIRUGEN, THE CARBOXYL TERMINUS OF HIRUDIN, WHICH OCCUPIES THE EXOSITE. THE INHIBITOR 00K IS COVALENTLY CONNECTED TO SER 195 OF THE ENZYME TO FORM A HEMIKETAL.
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: 2.4 Å3/Da / Density % sol: 51 %
Crystal growMethod: vapor diffusion - hanging drop, macroseeding / pH: 7.3
Details: 0.1 M SODIUM PHOSPHATE BUFFER, PH 7.3, 27-28 % PEG 8000, HANGING DROPS AND MACROSEEDING; THEN SOAKED IN PEG-PHOSPHATE-0.1 M NACL, AND THE MOL 106 INHIBITOR WAS ADDED IN 3 STEPS WITH FINAL ...Details: 0.1 M SODIUM PHOSPHATE BUFFER, PH 7.3, 27-28 % PEG 8000, HANGING DROPS AND MACROSEEDING; THEN SOAKED IN PEG-PHOSPHATE-0.1 M NACL, AND THE MOL 106 INHIBITOR WAS ADDED IN 3 STEPS WITH FINAL CONC. 7.3 MM, vapor diffusion - hanging drop and macroseeding
Crystal grow
*PLUS
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 %(v/v)PEG80001reservoir

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH2R / Wavelength: 1.5418
DetectorType: SIEMENS / Detector: AREA DETECTOR / Date: May 15, 1995 / Details: COLLIMATOR
RadiationMonochromator: GRAPHITE(002) / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionHighest resolution: 2.12 Å / Num. obs: 18219 / % possible obs: 86 % / Redundancy: 3 % / Rmerge(I) obs: 0.044 / Net I/σ(I): 23.8
Reflection shellResolution: 2.12→2.26 Å / Redundancy: 1.7 % / Rmerge(I) obs: 0.229 / Mean I/σ(I) obs: 3.5 / % possible all: 60
Reflection
*PLUS
Num. measured all: 54609
Reflection shell
*PLUS
% possible obs: 60 %

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Processing

Software
NameClassification
XENGENdata collection
XENGENdata reduction
PROFFTrefinement
XENGENdata scaling
RefinementMethod to determine structure: PREVIOUS STRUCTURE
Starting model: PDB ENTRY 1HAH

1hah


Resolution: 2.12→7 Å / σ(F): 4
RfactorNum. reflection% reflection
Rwork0.155 --
obs-15585 75 %
Displacement parametersBiso mean: 24 Å2
Refinement stepCycle: LAST / Resolution: 2.12→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2298 0 40 165 2503
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONp_bond_d0.020.02
X-RAY DIFFRACTIONp_angle_d0.0420.03
X-RAY DIFFRACTIONp_angle_deg
X-RAY DIFFRACTIONp_planar_d0.0490.045
X-RAY DIFFRACTIONp_hb_or_metal_coord
X-RAY DIFFRACTIONp_mcbond_it11
X-RAY DIFFRACTIONp_mcangle_it1.71.5
X-RAY DIFFRACTIONp_scbond_it2.42
X-RAY DIFFRACTIONp_scangle_it3.52.5
X-RAY DIFFRACTIONp_plane_restr0.0280.03
X-RAY DIFFRACTIONp_chiral_restr0.190.15
X-RAY DIFFRACTIONp_singtor_nbd0.220.6
X-RAY DIFFRACTIONp_multtor_nbd0.260.6
X-RAY DIFFRACTIONp_xhyhbond_nbd
X-RAY DIFFRACTIONp_xyhbond_nbd0.250.6
X-RAY DIFFRACTIONp_planar_tor43
X-RAY DIFFRACTIONp_staggered_tor2115
X-RAY DIFFRACTIONp_orthonormal_tor
X-RAY DIFFRACTIONp_transverse_tor3020
X-RAY DIFFRACTIONp_special_tor
Software
*PLUS
Name: PROFFT / Classification: refinement
Refinement
*PLUS
Rfactor obs: 0.155
Solvent computation
*PLUS
Displacement parameters
*PLUS

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