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- PDB-2feq: orally active thrombin inhibitors -

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Basic information

Entry
Database: PDB / ID: 2feq
Titleorally active thrombin inhibitors
Components
  • Decapeptide Hirudin Analogue
  • Thrombin heavy chain
  • Thrombin light chain
KeywordsHYDROLASE/HYDROLASE INHIBITOR / thrombin inhibitor / 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 / N-(carboxymethyl)-3-cyclohexyl-D-alanyl-N-({4-[(E)-amino(imino)methyl]-1,3-thiazol-2-yl}methyl)-L-prolinamide / Chem-34P / Prothrombin
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
Synthetic (others)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.44 Å
AuthorsMack, H. / Baucke, D. / Hornberger, W. / Lange, U.E.W. / Hoeffken, H.W.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Orally active thrombin inhibitors. Part 1: optimization of the P1-moiety
Authors: Mack, H. / Baucke, D. / Hornberger, W. / Lange, U.E.W. / Seitz, W. / Hoeffken, H.W.
History
DepositionDec 16, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 8, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 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 18, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Apr 4, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Thrombin light chain
H: Thrombin heavy chain
D: Decapeptide Hirudin Analogue
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8564
Polymers35,3913
Non-polymers4651
Water1,802100
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4580 Å2
ΔGint-12 kcal/mol
Surface area13050 Å2
MethodPISA
2
L: Thrombin light chain
H: Thrombin heavy chain
D: Decapeptide Hirudin Analogue
hetero molecules

L: Thrombin light chain
H: Thrombin heavy chain
D: Decapeptide Hirudin Analogue
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,7128
Polymers70,7836
Non-polymers9292
Water1086
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_555-x,y,-z1
Buried area10240 Å2
ΔGint-23 kcal/mol
Surface area25010 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/peptide Thrombin light chain /


Mass: 4096.534 Da / Num. of mol.: 1 / 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 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Decapeptide Hirudin Analogue


Type: Oligopeptide / Class: Anticoagulant, Antithrombotic / Mass: 1514.605 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: deduced from C-terminus of hirudin
Source: (natural) Hirudo medicinalis (medicinal leech), (synth.) Synthetic (others)
References: HIRUDIN ANALOGUE
#4: Chemical ChemComp-34P / N-(CARBOXYMETHYL)-3-CYCLOHEXYL-D-ALANYL-N-({4-[(E)-AMINO(IMINO)METHYL]-1,3-THIAZOL-2-YL}METHYL)-L-PROLINAMIDE


Type: peptide-like, Peptide-like / Class: Thrombin inhibitor / Mass: 464.582 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H32N6O4S
References: N-(carboxymethyl)-3-cyclohexyl-D-alanyl-N-({4-[(E)-amino(imino)methyl]-1,3-thiazol-2-yl}methyl)-L-prolinamide
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 100 / 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: 2.61 Å3/Da / Density % sol: 52.9 %
Crystal growTemperature: 298 K / Method: evaporation / pH: 8.5
Details: PEG 8000, Na-acetate, Tris, pH 8.5, EVAPORATION, temperature 298.0K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: SIEMENS HI-STAR / Detector: AREA DETECTOR / Date: Sep 12, 1997 / 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: 2.44→50.3 Å / Num. all: 13551 / Num. obs: 12441 / % possible obs: 91.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.56 % / Biso Wilson estimate: 37.3 Å2 / Rmerge(I) obs: 0.09 / Rsym value: 0.077 / Net I/σ(I): 10.3
Reflection shellResolution: 2.44→2.59 Å / Redundancy: 1.8 % / Rmerge(I) obs: 0.334 / Mean I/σ(I) obs: 2.3 / Num. unique all: 1208 / Rsym value: 0.249 / % possible all: 54.3

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Processing

Software
NameClassification
SAINTdata scaling
X-GENdata reduction
CNXrefinement
SAINTdata reduction
X-GENdata scaling
CNXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.44→50.3 Å / Isotropic thermal model: isotropic / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.242 613 -random
Rwork0.185 ---
all0.185 11967 --
obs0.185 11967 5.1 %-
Refine analyze
FreeObs
Luzzati coordinate error0.38 Å0.27 Å
Luzzati d res low-5 Å
Luzzati sigma a0.4 Å0.35 Å
Refinement stepCycle: LAST / Resolution: 2.44→50.3 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2361 0 32 100 2493
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_d1.4
X-RAY DIFFRACTIONc_dihedral_angle_d25.5
X-RAY DIFFRACTIONc_improper_angle_d0.86
LS refinement shellResolution: 2.44→2.59 Å / Rfactor Rfree error: 0.043
RfactorNum. reflection% reflection
Rfree0.317 55 -
Rwork0.28 --
obs-981 0.46 %

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