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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


induction of bacterial agglutination / blood coagulation, common pathway / fibrinogen complex / blood coagulation, fibrin clot formation / Regulation of TLR by endogenous ligand / platelet alpha granule / cellular response to leptin stimulus / MyD88 deficiency (TLR2/4) / positive regulation of heterotypic cell-cell adhesion / IRAK4 deficiency (TLR2/4) ...induction of bacterial agglutination / blood coagulation, common pathway / fibrinogen complex / blood coagulation, fibrin clot formation / Regulation of TLR by endogenous ligand / platelet alpha granule / cellular response to leptin stimulus / MyD88 deficiency (TLR2/4) / positive regulation of heterotypic cell-cell adhesion / IRAK4 deficiency (TLR2/4) / plasminogen activation / MyD88:MAL(TIRAP) cascade initiated on plasma membrane / negative regulation of astrocyte differentiation / : / thrombospondin receptor activity / p130Cas linkage to MAPK signaling for integrins / thrombin / thrombin-activated receptor signaling pathway / extracellular matrix structural constituent / Defective factor XII causes hereditary angioedema / positive regulation of peptide hormone secretion / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / positive regulation of phospholipase C-activating G protein-coupled receptor signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / GRB2:SOS provides linkage to MAPK signaling for Integrins / negative regulation of endothelial cell apoptotic process / protein secretion / positive regulation of collagen biosynthetic process / positive regulation of exocytosis / negative regulation of platelet activation / negative regulation of blood coagulation / cellular response to interleukin-1 / negative regulation of fibrinolysis / positive regulation of blood coagulation / negative regulation of proteolysis / negative regulation of extrinsic apoptotic signaling pathway via death domain receptors / positive regulation of vasoconstriction / Integrin cell surface interactions / positive regulation of substrate adhesion-dependent cell spreading / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / : / Gamma-carboxylation of protein precursors / Removal of aminoterminal propeptides from gamma-carboxylated proteins / protein polymerization / fibrinolysis / cell-matrix adhesion / regulation of cytosolic calcium ion concentration / : / Integrin signaling / negative regulation of cytokine production involved in inflammatory response / cell adhesion molecule binding / platelet alpha granule lumen / Regulation of Complement cascade / positive regulation of release of sequestered calcium ion into cytosol / positive regulation of receptor signaling pathway via JAK-STAT / positive regulation of protein secretion / acute-phase response / Cell surface interactions at the vascular wall / Peptide ligand-binding receptors / growth factor activity / Post-translational protein phosphorylation / response to wounding / lipopolysaccharide binding / platelet activation / response to calcium ion / positive regulation of protein localization to nucleus / Signaling by high-kinase activity BRAF mutants / MAP2K and MAPK activation / platelet aggregation / 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 / 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 / Signaling by BRAF and RAF1 fusions / Platelet degranulation / heparin binding / extracellular vesicle / Thrombin signalling through proteinase activated receptors (PARs) / protein-folding chaperone binding / ER-Phagosome pathway / protein-containing complex assembly / Dengue Virus-Host Interactions / antimicrobial humoral immune response mediated by antimicrobial peptide / extracellular matrix / blood microparticle / cell cortex / G alpha (q) signalling events / adaptive immune response / positive regulation of ERK1 and ERK2 cascade / protein-macromolecule adaptor activity / cell surface receptor signaling pathway / endoplasmic reticulum lumen / receptor ligand activity / Amyloid fiber formation
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/beta chain family / Fibrinogen alpha/beta chain family / Fibrinogen alpha chain / 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/beta chain family / Fibrinogen alpha/beta chain family / Fibrinogen alpha chain / Fibrinogen, conserved site / Fibrinogen C-terminal domain signature. / Fibrinogen-related domains (FReDs) / Fibrinogen beta and gamma chains, C-terminal globular domain / Fibrinogen, alpha/beta/gamma chain, C-terminal globular, subdomain 1 / 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 / Serine proteases, trypsin family, histidine active site. / Serine proteases, trypsin family, serine active site. / Peptidase S1A, chymotrypsin family / 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 / 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
Revision 1.8Nov 13, 2024Group: Structure summary / Category: 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
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

Has protein modificationY
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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