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- PDB-2c8y: thrombin inhibitors -

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Basic information

Entry
Database: PDB / ID: 2c8y
Titlethrombin inhibitors
Components
  • HIRUDIN VARIANT-2
  • THROMBIN HEAVY CHAIN
  • THROMBIN LIGHT CHAIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / PROTEASE / BLOOD COAGULATION / THROMBIN / ACUTE PHASE / DISEASE MUTATION / GAMMA-CARBOXYGLUTAMIC ACID / GLYCOPROTEIN / KRINGLE / PLASMA / SERINE PROTEASE / ZYMOGEN / 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
Chem-C3M / Prothrombin / Hirudin variant-2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
HIRUDO MEDICINALIS (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.2 Å
AuthorsHoward, N. / Abell, C. / Blakemore, W. / Carr, R. / Chessari, G. / Congreve, M. / Howard, S. / Jhoti, H. / Murray, C.W. / Seavers, L.C.A. / van Montfort, R.L.M.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Application of Fragment Screening and Fragment Linking to the Discovery of Novel Thrombin Inhibitors
Authors: Howard, N. / Abell, C. / Blakemore, W. / Chessari, G. / Congreve, M. / Howard, S. / Jhoti, H. / Murray, C.W. / Seavers, L.C.A. / Van Montfort, R.L.M.
History
DepositionDec 8, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 4, 2006Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.2Jan 15, 2014Group: Derived calculations / Other
Revision 1.3Jun 28, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.4Dec 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_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.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.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.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_type.id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Remark 700 SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" IN EACH CHAIN ON SHEET RECORDS BELOW ... SHEET DETERMINATION METHOD: DSSP THE SHEETS PRESENTED AS "BB" 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 LIGHT CHAIN
B: THROMBIN HEAVY CHAIN
I: HIRUDIN VARIANT-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)36,0538
Polymers35,4253
Non-polymers6285
Water5,368298
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4070 Å2
ΔGint-22.3 kcal/mol
Surface area15440 Å2
MethodPQS
Unit cell
Length a, b, c (Å)70.731, 71.516, 72.422
Angle α, β, γ (deg.)90.00, 100.51, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11B-2098-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules AI

#1: Protein/peptide THROMBIN LIGHT CHAIN


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: FRAGMENT ALPHA THROMBIN, RESIDUES 328-363 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin
#3: Protein/peptide HIRUDIN VARIANT-2 / HIRUGEN


Mass: 1548.580 Da / Num. of mol.: 1 / Fragment: PEPTIDE FRAGMENT OF HIRUDIN, RESIDUES 61-72 / Source method: isolated from a natural source / Source: (natural) HIRUDO MEDICINALIS (medicinal leech) / References: UniProt: P09945

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Protein , 1 types, 1 molecules B

#2: Protein THROMBIN HEAVY CHAIN


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: FRAGMENT ALPHA THROMBIN, RESIDUES 364-622 / Source method: isolated from a natural source / Source: (natural) HOMO SAPIENS (human) / Tissue: BLOOD PLASMA / References: UniProt: P00734, thrombin

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Non-polymers , 4 types, 303 molecules

#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-C3M / N-[(2R,3S)-3-AMINO-2-HYDROXY-4-PHENYLBUTYL]NAPHTHALENE-2-SULFONAMIDE / INHIBITOR OF THROMBIN


Mass: 370.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H22N2O3S
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 298 / Source method: isolated from a natural source / Formula: H2O

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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: 2.38 Å3/Da / Density % sol: 47.98 %
Crystal growpH: 7.3 / Details: PH 7.30

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.54
DetectorType: RIGAKU CCD / Detector: CCD / Details: CONFOCAL MULTILAYER
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.2→29.22 Å / Num. obs: 18049 / % possible obs: 99.7 % / Redundancy: 2.91 % / Rmerge(I) obs: 0.13 / Net I/σ(I): 5.3
Reflection shellResolution: 2.2→2.28 Å / Redundancy: 2.82 % / Rmerge(I) obs: 0.44 / Mean I/σ(I) obs: 2.2 / % possible all: 99.1

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Processing

Software
NameVersionClassification
REFMAC5.2.0019Crefinement
d*TREKdata reduction
d*TREKdata scaling
IN-HOUSESOFTWAREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1QJ1

1qj1


Resolution: 2.2→29.22 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.911 / SU B: 6.723 / SU ML: 0.168 / Cross valid method: THROUGHOUT / ESU R: 0.27 / ESU R Free: 0.231 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. ELECTRON DENSITY PEAKS CLOSE TO PHE 181 B, GLY 193 B AND PHE 204 B MODELLED AS DMSO
RfactorNum. reflection% reflectionSelection details
Rfree0.259 916 5.1 %RANDOM
Rwork0.185 ---
obs0.188 17132 99.7 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 26.73 Å2
Baniso -1Baniso -2Baniso -3
1-0.5 Å20 Å2-1.52 Å2
2---0.45 Å20 Å2
3----0.61 Å2
Refinement stepCycle: LAST / Resolution: 2.2→29.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2362 0 39 298 2699
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0120.0222459
X-RAY DIFFRACTIONr_bond_other_d0.0020.021732
X-RAY DIFFRACTIONr_angle_refined_deg1.3861.9833319
X-RAY DIFFRACTIONr_angle_other_deg0.8553.0044179
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3755286
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.33823.719121
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.23915.137437
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.2831520
X-RAY DIFFRACTIONr_chiral_restr0.0850.2341
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.022675
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02503
X-RAY DIFFRACTIONr_nbd_refined0.2020.2497
X-RAY DIFFRACTIONr_nbd_other0.1920.21849
X-RAY DIFFRACTIONr_nbtor_refined0.1830.21157
X-RAY DIFFRACTIONr_nbtor_other0.0820.21287
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1060.289
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0630.29
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2580.241
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1390.28
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.05851444
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it0.0862328
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.08361015
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.0997.5991
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: 2.2→2.26 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.328 77
Rwork0.236 1212

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