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- PDB-3ldx: Discovery and Clinical Evaluation of RWJ-671818, a Thrombin Inhib... -

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Basic information

Entry
Database: PDB / ID: 3ldx
TitleDiscovery and Clinical Evaluation of RWJ-671818, a Thrombin Inhibitor with an Oxyguanidine P1 Motif
Components
  • Hirudin variant-1
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / BLOOD CLOTTING / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / BLOOD COAGULATION / SERINE PROTEASE
Function / homology
Function and homology information


negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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 / serine-type endopeptidase inhibitor 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
Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor hirudin / Hirudin/antistatin / Prothrombin/thrombin / Thrombin light chain / Thrombin light chain domain superfamily / : / Thrombin light chain / Kringle domain ...Hirudin / Proteinase inhibitor I14, hirudin / Thrombin inhibitor 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 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-NLI / Prothrombin / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.246 Å
AuthorsSpurlino, J.C.
CitationJournal: To be Published
Title: Discovery and Clinical Evaluation of RWJ-671818, a Thrombin Inhibitor with an Oxyguanidine P1 Motif
Authors: Spurlino, J.C.
History
DepositionJan 13, 2010Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 10, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 19, 2017Group: Advisory / Structure summary
Category: pdbx_molecule_features / pdbx_unobs_or_zero_occ_atoms

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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
I: Hirudin variant-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,7124
Polymers35,2883
Non-polymers4231
Water82946
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3240 Å2
ΔGint-15 kcal/mol
Surface area12710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.099, 72.008, 73.412
Angle α, β, γ (deg.)90.00, 101.06, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 4096.534 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / References: UniProt: P00734, thrombin
#2: Protein Thrombin heavy chain / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: F2 / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin variant-1 / Hirudin-1 / Hirudin-I / Lepirudin


Mass: 1411.465 Da / Num. of mol.: 1 / Fragment: residues 55-65 / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P01050
#4: Chemical ChemComp-NLI / N-[2-(carbamimidamidooxy)ethyl]-2-{3-[(2,2-difluoro-2-phenylethyl)amino]-6-methyl-2-oxopyrazin-1(2H)-yl}acetamide / RWJ-671818


Mass: 423.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H23F2N7O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 46 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.61 Å3/Da / Density % sol: 52.93 %

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Data collection

Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionLowest resolution: 50 Å / Num. obs: 16380

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Processing

SoftwareName: PHENIX / Version: (phenix.refine: dev_243) / Classification: refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.246→22.923 Å / SU ML: 0.29 / σ(F): 0.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2244 1537 9.94 %
Rwork0.1748 --
obs0.1797 15468 88.68 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 27.979 Å2 / ksol: 0.357 e/Å3
Refinement stepCycle: LAST / Resolution: 2.246→22.923 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2326 0 30 46 2402
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.012420
X-RAY DIFFRACTIONf_angle_d1.33262
X-RAY DIFFRACTIONf_dihedral_angle_d20.275932
X-RAY DIFFRACTIONf_chiral_restr0.088333
X-RAY DIFFRACTIONf_plane_restr0.011422
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2456-2.3180.33671250.23851116X-RAY DIFFRACTION79
2.318-2.40080.29191320.21711201X-RAY DIFFRACTION85
2.4008-2.49680.24161310.21451224X-RAY DIFFRACTION86
2.4968-2.61030.2851380.21391249X-RAY DIFFRACTION88
2.6103-2.74770.27981340.20541259X-RAY DIFFRACTION89
2.7477-2.91950.24071410.1961286X-RAY DIFFRACTION90
2.9195-3.14440.26141460.19441299X-RAY DIFFRACTION91
3.1444-3.45980.21341460.15361316X-RAY DIFFRACTION92
3.4598-3.95830.16711500.13331331X-RAY DIFFRACTION93
3.9583-4.97860.15551470.11661339X-RAY DIFFRACTION93
4.9786-22.92450.19061470.16151311X-RAY DIFFRACTION89

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