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- PDB-2cf9: Complex of recombinant human thrombin with an inhibitor -

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Basic information

Entry
Database: PDB / ID: 2cf9
TitleComplex of recombinant human thrombin with an inhibitor
Components
  • HIRUDIN IIIA
  • THROMBIN HEAVY CHAIN
  • THROMBIN LIGHT CHAIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / HYDROLASE/INHIBITOR / ACUTE PHASE / BLOOD COAGULATION / CALCIUM-BINDING / GLYCOPROTEIN / HYDOLASE / SERINE PROTEASE / SERINE PROTEASE INHIBITOR COMPLEX / COMPLEX HYDROLASE-INHIBITOR / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


positive regulation of lipid kinase activity / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / cytolysis by host of symbiont cells / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / 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 / 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 / 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 / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / 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 / Peptidase S1A, chymotrypsin family / Serine proteases, trypsin family, histidine active site. / 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
N-terminal Asp des-amino Hirudin-3A / Chem-348 / Prothrombin / Hirudin-3A'
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.79 Å
AuthorsSchweizer, E. / Hoffmann-Roeder, A. / Olsen, J.A. / Obst-Sander, U. / Wagner, B. / Kansy, M. / Banner, D.W. / Diederich, F.
CitationJournal: Org.Biomol.Chem. / Year: 2006
Title: Multipolar Interactions in the D Pocket of Thrombin: Large Differences between Tricyclic Imide and Lactam Inhibitors.
Authors: Schweizer, E. / Hoffmann-Roeder, A. / Olsen, J.A. / Seiler, P. / Obst-Sander, U. / Wagner, B. / Kansy, M. / Banner, D.W. / Diederich, F.
History
DepositionFeb 17, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 14, 2006Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Advisory / Atomic model ...Advisory / Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Nov 30, 2012Group: Other
Revision 1.3Aug 7, 2013Group: Derived calculations / Other
Revision 1.4Oct 23, 2013Group: Other
Revision 1.5Mar 29, 2017Group: Structure summary
Revision 1.6Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.7Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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_comp_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr2_label_atom_id / _pdbx_struct_conn_angle.ptnr2_label_comp_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_conn_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: THROMBIN HEAVY CHAIN
I: HIRUDIN IIIA
L: THROMBIN LIGHT CHAIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,8046
Polymers34,2943
Non-polymers5103
Water8,899494
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3550 Å2
ΔGint-20.2 kcal/mol
Surface area15560 Å2
MethodPQS
Unit cell
Length a, b, c (Å)71.290, 71.840, 73.060
Angle α, β, γ (deg.)90.00, 100.56, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-2159-

HOH

21H-2385-

HOH

31I-2012-

HOH

41L-2064-

HOH

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Components

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Protein , 1 types, 1 molecules H

#1: Protein THROMBIN HEAVY CHAIN


Mass: 29594.055 Da / Num. of mol.: 1 / Fragment: CATALYTIC, RESIDUES 364-620
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): OVARY / Production host: CRICETULUS GRISEUS (Chinese hamster) / References: UniProt: P00734, thrombin

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Protein/peptide , 2 types, 2 molecules IL

#2: Protein/peptide HIRUDIN IIIA


Type: Oligopeptide / Class: Anticoagulant, Antithrombotic / Mass: 1396.450 Da / Num. of mol.: 1 / Fragment: C-TERMINUS, RESIDUES 55-65 / Source method: obtained synthetically / Source: (synth.) HIRUDO MEDICINALIS (medicinal leech)
References: UniProt: P28508, N-terminal Asp des-amino Hirudin-3A
#3: Protein/peptide THROMBIN LIGHT CHAIN


Mass: 3303.715 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN, RESIDUES 334-361
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Cell line (production host): OVARY / Production host: CRICETULUS GRISEUS (Chinese hamster) / References: UniProt: P00734, thrombin

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Non-polymers , 4 types, 497 molecules

#4: Chemical ChemComp-348 / 4-[(1R,3AS,4R,8AS,8BR)-1-ISOPROPYL-2-(4-METHOXYBENZYL)-3-OXODECAHYDROPYRROLO[3,4-A]PYRROLIZIN-4-YL]BENZENECARBOXIMIDAMIDE


Mass: 446.584 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H34N4O2
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 494 / Source method: isolated from a natural source / Formula: H2O

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Details

Compound detailsTHROMBIN CLEAVES BONDS AFTER ARG AND LYS, CONVERTS FIBRINOGEN TO FIBRIN AND ACTIVATES FACTORS V, ...THROMBIN CLEAVES BONDS AFTER ARG AND LYS, CONVERTS FIBRINOGEN TO FIBRIN AND ACTIVATES FACTORS V, VII, VIII, XIII HIRUDIN IS A POTENT THROMBIN-SPECIFIC PROTEASE INHIBITOR

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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: 2.76 Å3/Da / Density % sol: 43 %
Crystal growpH: 7.4 / Details: PH 7.40

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: CCD / Date: Oct 16, 2004 / Details: OSMIC MIRRORS
RadiationMonochromator: OSMIC MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.79→20 Å / Num. obs: 31281 / % possible obs: 91.4 % / Observed criterion σ(I): -3 / Redundancy: 4.54 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 22.9
Reflection shellResolution: 1.79→1.9 Å / Redundancy: 4.13 % / Rmerge(I) obs: 0.25 / Mean I/σ(I) obs: 5.4 / % possible all: 86.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1OYT

1oyt


Resolution: 1.79→71.8 Å / Cor.coef. Fo:Fc: 0.965 / Cor.coef. Fo:Fc free: 0.945 / SU B: 4.636 / SU ML: 0.078 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 0.118 / ESU R Free: 0.115 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: THE SIDE CHAIN OF ARG 75 HAS ALTERNATIVE CONFORMATIONS, ONE OF WHICH IS ON A DIAD AXIS. IT HAS NOT BEEN MODELLED.
RfactorNum. reflection% reflectionSelection details
Rfree0.198 1582 5.1 %RANDOM
Rwork0.16 ---
obs0.162 29702 91.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.94 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å2-0.8 Å2
2---0.44 Å20 Å2
3---0.14 Å2
Refinement stepCycle: LAST / Resolution: 1.79→71.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2301 0 35 494 2830
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222398
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.3591.9823242
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.1175280
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.10223.482112
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.60815420
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.7181519
X-RAY DIFFRACTIONr_chiral_restr0.090.2338
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021822
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.190.21040
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3070.21580
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1350.2341
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.150.214
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1750.225
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.591.51412
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.03522276
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.60731039
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it2.4984.5966
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.79→1.84 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.248 124
Rwork0.205 2053
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.5375-0.5342-0.23241.455-0.94982.74590.0212-0.0020.02710.081-0.04240.0644-0.1207-0.15230.0212-0.02140.0240.0282-0.0431-0.016-0.01430.04410.84624.919
21.171-0.5340.12920.8758-0.1270.8150.05440.0483-0.0544-0.0237-0.04120.01750.0510.0489-0.0132-0.03570.01650.0032-0.0412-0.0112-0.034214.257-0.90520.033
34.76993.198-1.73992.44740.287510.46530.16560.14-0.117-1.0186-0.7449-0.40420.9320.45810.57930.03160.1012-0.05240.0485-0.0620.03018.255-4.799-1.564
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1L1 - 14
2X-RAY DIFFRACTION2H16 - 245
3X-RAY DIFFRACTION3I1 - 6

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