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- PDB-2a2x: Orally Active Thrombin Inhibitors in Complex with Thrombin Inh12 -

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Basic information

Entry
Database: PDB / ID: 2a2x
TitleOrally Active Thrombin Inhibitors in Complex with Thrombin Inh12
Components
  • Thrombin heavy chain
  • Thrombin light chain
  • synthetic peptidePeptide synthesis
KeywordsHYDROLASE/HYDROLASE INHIBITOR / blood clotting / serine protease / HYDROLASE-hydrolase inhibitor COMPLEX
Function / homology
Function and homology information


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 / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin ...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 / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / ligand-gated ion channel signaling pathway / Defective F8 cleavage by thrombin / Platelet Aggregation (Plug Formation) / negative regulation of platelet activation / negative regulation of astrocyte differentiation / 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 / Regulation of Complement cascade / acute-phase response / Cell surface interactions at the vascular wall / lipopolysaccharide binding / negative regulation of proteolysis / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / positive regulation of insulin secretion / platelet activation / response to wounding / Golgi lumen / positive regulation of protein localization to nucleus / 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 / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / calcium ion binding / positive regulation of cell population proliferation / 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. / Kringle 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 / 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 / Beta Barrel / Mainly Beta
Similarity search - Domain/homology
HIRUDIN ANALOGUE / Chem-NA9 / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
Synthetic (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsLange, U.E.W. / Baucke, D. / Hornberger, W. / Mack, H. / Seitz, W. / Hoeffken, H.W.
CitationJournal: BIOORG.MED.CHEM.LETT. / Year: 2006
Title: Orally active thrombin inhibitors. Part 2: optimization of the P2-moiety
Authors: Lange, U.E.W. / Baucke, D. / Hornberger, W. / Mack, H. / Seitz, W. / Hoeffken, H.W.
History
DepositionJun 23, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 14, 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 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software / Item: _software.classification
Revision 1.5Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.6Aug 23, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _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

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Assembly

Deposited unit
L: Thrombin light chain
H: Thrombin heavy chain
P: synthetic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,5904
Polymers35,1433
Non-polymers4471
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5010 Å2
ΔGint-13 kcal/mol
Surface area12740 Å2
MethodPISA
2
L: Thrombin light chain
H: Thrombin heavy chain
P: synthetic peptide
hetero molecules

L: Thrombin light chain
H: Thrombin heavy chain
P: synthetic peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,1798
Polymers70,2866
Non-polymers8932
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area11090 Å2
ΔGint-23 kcal/mol
Surface area24420 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.240, 72.390, 73.060
Angle α, β, γ (deg.)90, 101.01, 90
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide Thrombin light chain /


Mass: 3848.256 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734
#2: Protein Thrombin heavy chain / / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide synthetic peptide / Peptide synthesis


Type: Oligopeptide / Class: Anticoagulant, Antithrombotic / Mass: 1514.605 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: Synthetic peptide / Source: (synth.) Synthetic (others) / References: HIRUDIN ANALOGUE
#4: Chemical ChemComp-NA9 / N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({6-[AMINO(IMINO)METHYL]PYRIDIN-3-YL}METHYL)-N~2~-METHYL-L-ALANINAMIDE / 2-((R)-1-(((S)-1-((6-CARBAMIMIDOYLPYRIDIN-3-YL)METHYLAMINO)-1-OXOPROPAN-2-YL)(METHYL)AMINO)-3-CYCLOHEXYL-1-OXOPROPAN-2- YLAMINO)ACETIC ACID


Mass: 446.543 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H34N6O4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 174 / 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: 2.64 Å3/Da / Density % sol: 53.47 %
Crystal growTemperature: 298 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: PEG 400, Na-acetate, Tris, pH 8.5, VAPOR DIFFUSION, SITTING DROP, temperature 298K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: SIEMENS / Detector: CCD / Date: Apr 22, 1997 / Details: Goebel Mirror
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.44→500 Å / Num. all: 18112 / Num. obs: 11993

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Processing

Software
NameVersionClassificationNB
CNSrefinement
PDB_EXTRACT1.601data extraction
FRAMBOdata collection
SAINTdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1NZQ

1nzq


Resolution: 2.44→500 Å / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.221 613 4.6 %random
Rwork0.198 ---
all-18112 --
obs-11993 89.1 %-
Displacement parametersBiso mean: 34.466 Å2
Baniso -1Baniso -2Baniso -3
1--0.034 Å20 Å20.129 Å2
2--0.02 Å20 Å2
3---0.014 Å2
Refinement stepCycle: LAST / Resolution: 2.44→500 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2400 0 32 174 2606
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paramprotein.top
X-RAY DIFFRACTION2nnas.paramnnas.top
X-RAY DIFFRACTION3water_rep.paramwater.top
X-RAY DIFFRACTION4ion.paramion.top
X-RAY DIFFRACTION5inh.paraminh.top

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