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- PDB-2anm: Ternary complex of an orally active thrombin inhibitor with human... -

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Basic information

Entry
Database: PDB / ID: 2anm
TitleTernary complex of an orally active thrombin inhibitor with human thrombin and a c-terminal hirudin derived exo-sit inhibitor
Components(thrombin) x 2
KeywordsBLOOD CLOTTING
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
Chem-CDO / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.4 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
DepositionAug 11, 2005Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 13, 2006Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: thrombin
L: thrombin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1473
Polymers33,6912
Non-polymers4571
Water3,135174
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3510 Å2
ΔGint-10 kcal/mol
Surface area12580 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.240, 72.390, 73.060
Angle α, β, γ (deg.)90.00, 101.01, 90.00
Int Tables number5
Space group name H-MC121

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Components

#1: Protein thrombin / Coagulation factor II


Mass: 29594.055 Da / Num. of mol.: 1 / Fragment: Thrombin heavy chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#2: Protein/peptide thrombin / Coagulation factor II


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: Thrombin light chain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli) / References: UniProt: P00734, thrombin
#3: Chemical ChemComp-CDO / 2-((R)-1-((S)-2-(N-(6-CARBAMIMIDOYLPYRIDIN-3-YL)METHYLCARBAMOYL)-2H-PYRROL-1(5H)-YL)-3-CYCLOHEXYL-1-OXOPROPAN-2-YLAMINO)ACETIC ACID


Mass: 456.538 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H32N6O4
#4: Water ChemComp-HOH / 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: 2.74 Å3/Da / Density % sol: 55.16 %

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200HB / Wavelength: 1.5418 Å
DetectorType: SIEMENS / Detector: CCD / Details: goebel mirror
RadiationMonochromator: goebel mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→45 Å / Num. all: 64174 / Num. obs: 18187 / % possible obs: 98 % / Observed criterion σ(F): 2 / Biso Wilson estimate: 23.9 Å2 / Rmerge(I) obs: 0.0938 / Net I/σ(I): 9.39
Reflection shellResolution: 2.4→2.57 Å / Rmerge(I) obs: 0.373 / % possible all: 93

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Processing

Software
NameVersionClassification
CNX2002refinement
X-GENdata reduction
X-GENdata scaling
CNX2002phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→44.13 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 118200.48 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.25 650 4.9 %RANDOM
Rwork0.194 ---
obs-13324 92.7 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 50.6073 Å2 / ksol: 0.34422 e/Å3
Displacement parametersBiso mean: 37.7 Å2
Baniso -1Baniso -2Baniso -3
1-7.61 Å20 Å2-7.92 Å2
2--0.17 Å20 Å2
3----7.78 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.36 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.47 Å0.39 Å
Refinement stepCycle: LAST / Resolution: 2.4→44.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2295 0 33 174 2502
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d23.9
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.83
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.81.5
X-RAY DIFFRACTIONc_mcangle_it3.192
X-RAY DIFFRACTIONc_scbond_it2.082
X-RAY DIFFRACTIONc_scangle_it3.252.5
LS refinement shellResolution: 2.4→2.55 Å / Rfactor Rfree error: 0.035 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.347 96 4.7 %
Rwork0.299 1942 -
obs--85.2 %
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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