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- PDB-2a45: Crystal structure of the complex between thrombin and the central... -

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Basic information

Entry
Database: PDB / ID: 2a45
TitleCrystal structure of the complex between thrombin and the central "E" region of fibrin
Components
  • Fibrinogen alpha chain
  • Fibrinogen beta chain
  • Fibrinogen gamma chain
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / THROMBIN / FIBRIN / FRAGMENT E / THROMBIN-FIBRIN COMPLEX / COILED COILS / DISULFIDE RINGS / BLOOD CLOTTING / HYDROLASE-HYDROLASE INHIBITOR COMPLEX
Function / homology
Function and homology information


platelet maturation / blood coagulation, common pathway / induction of bacterial agglutination / fibrinogen complex / Regulation of TLR by endogenous ligand / platelet alpha granule / blood coagulation, fibrin clot formation / cellular response to leptin stimulus / cellular response to interleukin-6 / MyD88 deficiency (TLR2/4) ...platelet maturation / blood coagulation, common pathway / induction of bacterial agglutination / fibrinogen complex / Regulation of TLR by endogenous ligand / platelet alpha granule / blood coagulation, fibrin clot formation / cellular response to leptin stimulus / cellular response to interleukin-6 / MyD88 deficiency (TLR2/4) / positive regulation of heterotypic cell-cell adhesion / IRAK4 deficiency (TLR2/4) / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / extracellular matrix structural constituent / plasminogen activation / p130Cas linkage to MAPK signaling for integrins / positive regulation of lipid kinase activity / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / cytolysis by host of symbiont cells / thrombospondin receptor activity / Defective factor XII causes hereditary angioedema / thrombin / positive regulation of peptide hormone secretion / regulation of blood coagulation / positive regulation of exocytosis / neutrophil-mediated killing of gram-negative bacterium / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of astrocyte differentiation / protein secretion / protein polymerization / negative regulation of platelet activation / positive regulation of collagen biosynthetic process / negative regulation of cytokine production involved in inflammatory response / cellular response to interleukin-1 / Integrin cell surface interactions / 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 / negative regulation of endothelial cell apoptotic process / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of substrate adhesion-dependent cell spreading / positive regulation of vasoconstriction / cell adhesion molecule binding / fibrinolysis / regulation of cytosolic calcium ion concentration / Intrinsic Pathway of Fibrin Clot Formation / Integrin signaling / Peptide ligand-binding receptors / cell-matrix adhesion / positive regulation of release of sequestered calcium ion into cytosol / platelet alpha granule lumen / acute-phase response / Regulation of Complement cascade / positive regulation of protein secretion / negative regulation of proteolysis / Cell surface interactions at the vascular wall / lipopolysaccharide binding / Post-translational protein phosphorylation / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / positive regulation of insulin secretion / platelet activation / platelet aggregation / response to wounding / positive regulation of protein localization to nucleus / response to calcium ion / Golgi lumen / antimicrobial humoral immune response mediated by antimicrobial peptide / Signaling by RAF1 mutants / Signaling by moderate kinase activity BRAF mutants / Paradoxical activation of RAF signaling by kinase inactive BRAF / Signaling downstream of RAS mutants / 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 / Signaling by BRAF and RAF1 fusions / extracellular vesicle / blood coagulation / Thrombin signalling through proteinase activated receptors (PARs) / Platelet degranulation / heparin binding / cell cortex / regulation of cell shape / ER-Phagosome pathway / protein-folding chaperone binding / positive regulation of cell growth / G alpha (q) signalling events / protein-containing complex assembly / collagen-containing extracellular matrix / adaptive immune response / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #50 / Fibrinogen alpha C domain / Fibrinogen alpha C domain / Fibrinogen, alpha/beta/gamma chain, coiled coil domain / Fibrinogen alpha chain / Fibrinogen alpha/beta chain family / Fibrinogen alpha/beta chain family / Fibrinogen, conserved site / Fibrinogen C-terminal domain signature. / Fibrinogen-related domains (FReDs) ...Single alpha-helices involved in coiled-coils or other helix-helix interfaces - #50 / Fibrinogen alpha C domain / Fibrinogen alpha C domain / Fibrinogen, alpha/beta/gamma chain, coiled coil domain / Fibrinogen alpha chain / Fibrinogen alpha/beta chain family / Fibrinogen alpha/beta chain family / Fibrinogen, conserved site / Fibrinogen C-terminal domain signature. / Fibrinogen-related domains (FReDs) / Fibrinogen, alpha/beta/gamma chain, C-terminal globular, subdomain 1 / Fibrinogen beta and gamma chains, C-terminal globular domain / Fibrinogen, alpha/beta/gamma chain, C-terminal globular domain / Fibrinogen-like, C-terminal / Fibrinogen C-terminal domain profile. / 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 / Single alpha-helices involved in coiled-coils or other helix-helix interfaces / 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 domain profile. / Serine proteases, trypsin family, serine active site. / 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 / Up-down Bundle / Beta Barrel / Mainly Beta / Mainly Alpha
Similarity search - Domain/homology
D-Phe-Pro-Arg-CH2Cl / Chem-0G6 / PHOSPHATE ION / Prothrombin / Fibrinogen alpha chain / Fibrinogen beta chain / Fibrinogen gamma chain
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 3.65 Å
AuthorsPechik, I. / Madrazo, J. / Gilliland, G.L. / Medved, L.
Citation
Journal: Biochemistry / Year: 2006
Title: Structural basis for sequential cleavage of fibrinopeptides upon fibrin assembly.
Authors: Pechik, I. / Yakovlev, S. / Mosesson, M.W. / Gilliland, G.L. / Medved, L.
#1: Journal: Proc.Natl.Acad.Sci.USA / Year: 2004
Title: Crystal Structure of the Complex between Thrombin and the Central "E" Region of Fibrin
Authors: Pechik, I. / Madrazo, J. / Mosesson, M.W. / Hernandez, I. / Gilliland, G.L. / Medved, L.
History
DepositionJun 27, 2005Deposition site: RCSB / Processing site: RCSB
SupersessionMay 2, 2006ID: 1QVH
Revision 1.0May 2, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 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 1.3Feb 27, 2013Group: Other
Revision 1.4Oct 11, 2017Group: Advisory / Refinement description / Category: pdbx_unobs_or_zero_occ_residues / software / Item: _software.name
Revision 1.5Jul 24, 2019Group: Data collection / Derived calculations / Refinement description
Category: software / struct_conn
Item: _software.classification / _software.name / _struct_conn.pdbx_leaving_atom_flag
Revision 1.6Aug 14, 2019Group: Data collection / Refinement description / Category: computing / software / Item: _software.classification / _software.name
Revision 1.7Aug 23, 2023Group: Advisory / Data collection ...Advisory / 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_unobs_or_zero_occ_residues / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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_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: Thrombin light chain
E: Thrombin heavy chain
G: Fibrinogen alpha chain
H: Fibrinogen beta chain
I: Fibrinogen gamma chain
J: Fibrinogen alpha chain
K: Fibrinogen beta chain
L: Fibrinogen gamma chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)111,91814
Polymers110,82010
Non-polymers1,0984
Water00
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.263, 76.263, 192.452
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number144
Space group name H-MP31

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Components

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Protein/peptide , 2 types, 4 molecules ADIL

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


Mass: 4096.534 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#5: Protein/peptide Fibrinogen gamma chain


Mass: 5103.651 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Details: PROTEOLYTIC FRAGMENT / Source: (natural) Homo sapiens (human) / References: UniProt: P02679

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Protein , 3 types, 6 molecules BEGJHK

#2: Protein Thrombin heavy chain / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein Fibrinogen alpha chain


Mass: 6642.435 Da / Num. of mol.: 2 / Fragment: UNP P02671, residues 36-92 / Source method: isolated from a natural source / Details: PROTEOLYTIC FRAGMENT / Source: (natural) Homo sapiens (human) / References: UniProt: P02671
#4: Protein Fibrinogen beta chain


Mass: 9787.060 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Details: PROTEOLYTIC FRAGMENT / Source: (natural) Homo sapiens (human) / References: UniProt: P02675

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Non-polymers , 2 types, 4 molecules

#6: Chemical ChemComp-0G6 / D-phenylalanyl-N-[(2S,3S)-6-{[amino(iminio)methyl]amino}-1-chloro-2-hydroxyhexan-3-yl]-L-prolinamide / PRO2061 / PPACK


Type: peptide-like, Peptide-like / Class: Inhibitor / Mass: 453.986 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H34ClN6O3 / References: D-Phe-Pro-Arg-CH2Cl
#7: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: PO4

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Details

Nonpolymer detailsTHE INHIBITOR IS COVALENTLY CONNECTED TO ACTIVE_SITE RESIDUES: 1) VIA A HEMIKETAL GROUP TO OG SER ...THE INHIBITOR IS COVALENTLY CONNECTED TO ACTIVE_SITE RESIDUES: 1) VIA A HEMIKETAL GROUP TO OG SER 195 IN CHAINS B AND E, 2) VIA A METHYLENE GROUP TO NE2 HIS 57 IN CHAINS B AND E.
Sequence detailsHUMAN ALPHA THROMBIN COMPRISES AMINO ACID RESIDUES 1H TO 247 (CHYMOTRYPSIN NUMBERING). N-TERMINAL ...HUMAN ALPHA THROMBIN COMPRISES AMINO ACID RESIDUES 1H TO 247 (CHYMOTRYPSIN NUMBERING). N-TERMINAL SEQUENCES OF THE CENTRAL "E" REGION OF HUMAN FIBRIN START FROM RESIDUE 17 FOR ALPHA CHAINS (CHAINS G, J), 15 FOR BETA CHAINS (CHAINS H, K), AND 1 FOR GAMMA CHAINS (CHAINS I, L). C-TERMINAL SEQUENCES OF ALPHA, BETA, AND GAMMA CHAINS WERE NOT DETERMINED. DUE TO THE LACK OF ELECTRON DENSITY THROMBIN RESIDUES 1H THROUGH 1E AND RESIDUE 247 COULD NOT BE BUILD, AS WELL AS RESIDUES 17 THROUGH 28 OF FIBRIN ALPHA CHAINS, 15 THROUGH 53 OF FIBRIN BETA CHAINS, AND 1 THROUGH 5 OF FIBRIN GAMMA CHAINS.

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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: 2.89 Å3/Da / Density % sol: 55.58 %
Crystal growTemperature: 298 K / Method: microdialysis / pH: 7.9
Details: PEG 3500, AMMONIUM PHOSPHATE, TRIS, pH 7.90, MICRODIALYSIS, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: SIEMENS / Wavelength: 1.5418
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Details: COLLIMATOR
RadiationMonochromator: GRAPHITE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 3.65→31.24 Å / Num. obs: 26890 / % possible obs: 96.3 % / Net I/σ(I): 3.4
Reflection shellResolution: 3.65→3.78 Å / Mean I/σ(I) obs: 1.9 / % possible all: 87.6

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Processing

Software
NameVersionClassification
d*TREKdata scaling
d*TREKdata reduction
CNS1.1refinement
SHELXL-97refinement
CNS1.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entries 1PPB, 1JY2

1ppb

1jy2


Resolution: 3.65→19.7 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: ENGH & HUBER
Details: DIFFRACTION DATA WERE COLLECTED FROM MEROHEDRALLY TWINNED CRYSTAL. THE PRESENCE OF 38.2% TWIN FRACTION CORRESPONDING TO -H -H-K -L TWINNING OPERATOR WAS TAKEN INTO ACCOUNT IN THE REFINEMENT. ...Details: DIFFRACTION DATA WERE COLLECTED FROM MEROHEDRALLY TWINNED CRYSTAL. THE PRESENCE OF 38.2% TWIN FRACTION CORRESPONDING TO -H -H-K -L TWINNING OPERATOR WAS TAKEN INTO ACCOUNT IN THE REFINEMENT.RESIDUES THAT ADDED THROUGH THE MODELING EFFORTS (26 THROUGH 28, CHAINS G, J) ARE INCLUDED IN THE COORDINATES FOR COMPLETENESS. THEY HAVE BEEN ASSIGNED OCCUPANCIES AND TEMPERATURE FACTORS OF 0.0, AND THEY HAVE NO VISIBLE/INTERPRETABLE ELECTRON DENSITY ASSOCIATED WITH THEIR LOCATIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.29 2390 8.6 %RANDOM
obs0.221 -93.4 %-
all-25847 --
Solvent computationSolvent model: FLAT MODEL
Refinement stepCycle: LAST / Resolution: 3.65→19.7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6834 0 70 0 6904
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONs_bond_d0.013
X-RAY DIFFRACTIONs_angle_d
X-RAY DIFFRACTIONs_similar_dist
X-RAY DIFFRACTIONs_from_restr_planes
X-RAY DIFFRACTIONs_zero_chiral_vol
X-RAY DIFFRACTIONs_non_zero_chiral_vol
X-RAY DIFFRACTIONs_anti_bump_dis_restr
X-RAY DIFFRACTIONs_rigid_bond_adp_cmpnt
X-RAY DIFFRACTIONs_similar_adp_cmpnt
X-RAY DIFFRACTIONs_approx_iso_adps

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