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- PDB-3da9: Crystal structure of thrombin in complex with inhibitor -

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Basic information

Entry
Database: PDB / ID: 3da9
TitleCrystal structure of thrombin in complex with inhibitor
Components
  • Hirudin peptide
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE / thrombin / inhibitor complex / Acute phase / Blood coagulation / Calcium / Cleavage on pair of basic residues / Disease mutation / Gamma-carboxyglutamic acid / Glycoprotein / Kringle / Pharmaceutical / Polymorphism / Protease / Secreted / Serine protease / Zymogen
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 / 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
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 / 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
beta-phenyl-D-phenylalanyl-N-propyl-L-prolinamide / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsXue, Y. / Hansson, S.K.
CitationJournal: J.Med.Chem. / Year: 2009
Title: Compounds binding to the S2-S3 pockets of thrombin.
Authors: Nilsson, M. / Hamalainen, M. / Ivarsson, M. / Gottfries, J. / Xue, Y. / Hansson, S. / Isaksson, R. / Fex, T.
History
DepositionMay 29, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 19, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Apr 3, 2024Group: Data collection / Database references ...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_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_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_auth_seq_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
A: Thrombin light chain
B: Thrombin heavy chain
D: Hirudin peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4575
Polymers35,0553
Non-polymers4022
Water4,990277
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3400 Å2
ΔGint-28 kcal/mol
Surface area12790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.830, 71.455, 71.905
Angle α, β, γ (deg.)90.00, 100.35, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 2 types, 2 molecules AD

#1: Protein/peptide Thrombin light chain / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin light chain


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: UNP residues 328-363 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin peptide


Mass: 1178.095 Da / Num. of mol.: 1 / Source method: obtained synthetically

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Protein , 1 types, 1 molecules B

#2: Protein Thrombin heavy chain / Coagulation factor II / Activation peptide fragment 1 / Activation peptide fragment 2 / Thrombin heavy chain


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: UNP residues 364-622 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin

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Non-polymers , 3 types, 279 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-44U / beta-phenyl-D-phenylalanyl-N-propyl-L-prolinamide


Mass: 379.495 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29N3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 277 / 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: 2.58 Å3/Da / Density % sol: 52.4 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: The drop was made by mixing 1.5 ul of the thrombin-hirudin complex and 1.5 ul of reservior solution containing: Phosphate buffer pH7.3, 28% PEG, VAPOR DIFFUSION, HANGING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU300 / Wavelength: 1.5418 / Wavelength: 1.5418 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Sep 22, 2007
RadiationMonochromator: Mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→70.71 Å / Num. all: 32305 / Num. obs: 32305 / % possible obs: 100 % / Observed criterion σ(F): 1 / Observed criterion σ(I): 1 / Redundancy: 7.1 % / Biso Wilson estimate: 26.5 Å2 / Rmerge(I) obs: 0.07 / Rsym value: 0.065 / Net I/σ(I): 7.7
Reflection shellResolution: 1.8→1.85 Å / Redundancy: 6.9 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 1.4 / Num. unique all: 2424 / Rsym value: 0.53 / % possible all: 100

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MAR345dtbdata collection
MOSFLMdata reduction
SCALAdata scaling
CCP4phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: apo

Resolution: 1.8→70 Å / Cor.coef. Fo:Fc: 0.96 / Cor.coef. Fo:Fc free: 0.942 / SU B: 2.601 / SU ML: 0.081 / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0 / ESU R: 0.126 / ESU R Free: 0.119 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.21456 1570 5.1 %RANDOM
Rwork0.18222 ---
all0.18393 29462 --
obs0.18393 29462 96.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 33.85 Å2
Baniso -1Baniso -2Baniso -3
1-0.77 Å20 Å2-1.49 Å2
2---1.05 Å20 Å2
3----0.26 Å2
Refinement stepCycle: LAST / Resolution: 1.8→70 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2332 0 29 277 2638
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222422
X-RAY DIFFRACTIONr_angle_refined_deg1.3011.9773270
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8595283
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.69423.391115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.88815426
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.0961520
X-RAY DIFFRACTIONr_chiral_restr0.0890.2335
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021840
X-RAY DIFFRACTIONr_nbd_refined0.20.21122
X-RAY DIFFRACTIONr_nbtor_refined0.3120.21631
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1190.2233
X-RAY DIFFRACTIONr_metal_ion_refined0.0460.24
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.4290.224
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1780.217
X-RAY DIFFRACTIONr_mcbond_it0.7951.51424
X-RAY DIFFRACTIONr_mcangle_it1.48422295
X-RAY DIFFRACTIONr_scbond_it2.13831050
X-RAY DIFFRACTIONr_scangle_it3.4674.5975
LS refinement shellResolution: 1.8→1.847 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.253 109 -
Rwork0.254 1993 -
obs--86.86 %

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