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- PDB-3c27: Cyanofluorophenylacetamides as Orally Efficacious Thrombin Inhibitors -

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Basic information

Entry
Database: PDB / ID: 3c27
TitleCyanofluorophenylacetamides as Orally Efficacious Thrombin Inhibitors
Components
  • Hirudin-3A
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / Thrombin / Serine protease / Acute phase / Blood coagulation / Gamma-carboxyglutamic acid / Glycoprotein / Hydrolase / Kringle / Protease / Secreted / Zymogen / Protease inhibitor / Serine protease inhibitor / Sulfation / 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 / regulation of cytosolic calcium ion concentration / fibrinolysis / 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 / lipopolysaccharide binding / Cell surface interactions at the vascular wall / negative regulation of proteolysis / positive regulation of receptor signaling pathway via JAK-STAT / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / response to wounding / platelet activation / 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 / G alpha (q) signalling events / positive regulation of cell growth / collagen-containing extracellular matrix / blood microparticle / cell surface receptor signaling pathway / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / G protein-coupled receptor signaling pathway / positive regulation of protein phosphorylation / 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
Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / Thrombin light chain / Kringle domain / Kringle ...Thrombin inhibitor hirudin / Hirudin / Proteinase inhibitor I14, hirudin / Hirudin/antistatin / 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. / Trypsin-like serine protease / Serine proteases, trypsin family, serine active site. / 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-DKK / Prothrombin / Hirudin-2 / Hirudin-3A
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / Resolution: 2.182 Å
AuthorsSpurlino, J.C. / McMillan, M. / Lewandowski, F. / Milligan, C.
CitationJournal: To be Published
Title: Cyanofluorophenylacetamides as Orally Efficacious Thrombin Inhibitors
Authors: Kreuter, K.D. / Lee, L. / Lu, T. / Giardino, E.C. / Patel, S. / Haung, H. / Xu, G. / Fitzgerald, M. / Mohan, M. / Crysler, C. / Eisennagel, S. / Dasgupta, M. / McMillan, M. / Spurlino, J.C. ...Authors: Kreuter, K.D. / Lee, L. / Lu, T. / Giardino, E.C. / Patel, S. / Haung, H. / Xu, G. / Fitzgerald, M. / Mohan, M. / Crysler, C. / Eisennagel, S. / Dasgupta, M. / McMillan, M. / Spurlino, J.C. / Heubert, N. / Maryanoff, B.E. / Tomczuk, B.E. / Damiano, B.P. / Player, M.R.
History
DepositionJan 24, 2008Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 17, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Thrombin light chain
B: Thrombin heavy chain
H: Hirudin-3A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,7034
Polymers34,2673
Non-polymers4351
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3230 Å2
ΔGint-17 kcal/mol
Surface area12600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.854, 72.026, 72.987
Angle α, β, γ (deg.)90.000, 100.500, 90.000
Int Tables number5
Space group name H-MC121

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Components

#1: Protein/peptide Thrombin light chain /


Mass: 3075.470 Da / Num. of mol.: 1 / Fragment: unp residues 334-359 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#2: Protein Thrombin heavy chain /


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: UNP residues 364-622
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin-3A / Hirudin IIIA


Mass: 1411.465 Da / Num. of mol.: 1 / Fragment: unp residues 55-65
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28507, UniProt: P28504*PLUS
#4: Chemical ChemComp-DKK / N-[2-(carbamimidamidooxy)ethyl]-2-{6-cyano-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-fluorophenyl}acetamide


Mass: 435.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H20F3N7O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.67 Å3/Da / Density % sol: 53.97 %

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: MACSCIENCE / Wavelength: 1.54 Å
DetectorType: BRUKER SMART 6000 / Detector: CCD / Date: Jun 7, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 2.182→50.075 Å / Num. obs: 18406 / Biso Wilson estimate: 24.22 Å2

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Processing

Software
NameVersionClassificationNB
PHENIXrefinement
PDB_EXTRACT3.004data extraction
RefinementResolution: 2.182→50.075 Å / FOM work R set: 0.847 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.215 938 5.1 %
Rwork0.174 --
obs0.176 18406 97.2 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 45.631 Å2 / ksol: 0.354 e/Å3
Displacement parametersBiso max: 10.18 Å2 / Biso mean: 28.82 Å2 / Biso min: 100.11 Å2
Baniso -1Baniso -2Baniso -3
1--0.558 Å20 Å2-4.513 Å2
2--2.988 Å20 Å2
3----2.431 Å2
Refinement stepCycle: LAST / Resolution: 2.182→50.075 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2326 0 31 116 2473
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0092408
X-RAY DIFFRACTIONf_angle_d1.2323245
X-RAY DIFFRACTIONf_chiral_restr0.08332
X-RAY DIFFRACTIONf_plane_restr0.006419
X-RAY DIFFRACTIONf_dihedral_angle_d20.355927
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 7

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.182-2.2970.2731310.1922274240545
2.297-2.4410.2681460.1922511265751
2.441-2.6290.2341270.1982540266751
2.629-2.8940.2361260.1992535266151
2.894-3.3120.2851430.1982530267350
3.312-4.1730.1481320.1492498263050
4.173-50.0880.1781330.1492580271351

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