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- PDB-1nt1: thrombin in complex with selective macrocyclic inhibitor -

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Basic information

Entry
Database: PDB / ID: 1nt1
Titlethrombin in complex with selective macrocyclic inhibitor
Components
  • Hirudin
  • thrombin
KeywordsBLOOD CLOTTING/HYDROLASE INHIBITOR / thrombin inhibitor complex / BLOOD CLOTTING-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-T76 / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 2 Å
AuthorsNantermet, P.G. / Barrow, J.C. / Newton, C.L. / Pellicore, J.M. / Young, M. / Lewis, S.D. / Lucas, B.J. / Krueger, J.A. / McMasters, D.R. / Yan, Y. ...Nantermet, P.G. / Barrow, J.C. / Newton, C.L. / Pellicore, J.M. / Young, M. / Lewis, S.D. / Lucas, B.J. / Krueger, J.A. / McMasters, D.R. / Yan, Y. / Kuo, L.C. / Vacca, J.P. / Selnick, H.G.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2003
Title: Design and synthesis of potent and selective macrocyclic thrombin inhibitors
Authors: Nantermet, P.G. / Barrow, J.C. / Newton, C.L. / Pellicore, J.M. / Young, M. / Lewis, S.D. / Lucas, B.J. / Krueger, J.A. / McMasters, D.R. / Yan, Y. / Kuo, L.C. / Vacca, J.P. / Selnick, H.G.
History
DepositionJan 28, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 2, 2003Provider: repository / Type: Initial release
Revision 1.1Apr 29, 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 1.3Oct 11, 2017Group: Refinement description / Category: software

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: thrombin
H: Hirudin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9613
Polymers34,4562
Non-polymers5051
Water2,576143
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.1, 72.1, 73.2
Angle α, β, γ (deg.)90.0, 100.9, 90.0
Int Tables number5
Cell settingmonoclinic
Space group name H-MC121

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Components

#1: Protein thrombin / / E.C.3.4.21.5 / Coagulation factor II


Mass: 33079.965 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: plasma from blood / References: UniProt: P00734, thrombin
#2: Protein/peptide Hirudin /


Mass: 1376.441 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: 10 AA HIRUDIN ANALOGUE / References: UniProt: P28504
#3: Chemical ChemComp-T76 / (6R,21AS)-17-CHLORO-6-CYCLOHEXYL-2,3,6,7,10,11,19,20-OCTAHYDRO-1H,5H-PYRROLO[1,2-K][1,4,8,11,14]BENZOXATETRAAZA-CYCLOHEPTADECINE-5,8,12,21(9H,13H,21AH)-TETRONE


Mass: 505.006 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H33ClN4O5
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 143 / 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 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 7.3
Details: PEG 8000, sodium phosphate, pH 7.3, VAPOR DIFFUSION, HANGING DROP, temperature 298K
Crystal grow
*PLUS
Method: unknown

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS II / Detector: IMAGE PLATE / Date: Jul 27, 1999
RadiationMonochromator: Yale Mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2→50 Å / Num. obs: 19664 / % possible obs: 80 % / Rmerge(I) obs: 0.07

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Processing

Software
NameVersionClassification
SCALEPACKdata scaling
X-PLORmodel building
X-PLOR3.1refinement
X-PLORphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2→6 Å / Cross valid method: THROUGHOUT / σ(F): 0 / σ(I): 0
RfactorNum. reflectionSelection details
Rwork0.19 --
all0.191 17234 -
obs0.191 17234 -
Rfree--random
Refinement stepCycle: LAST / Resolution: 2→6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2328 0 35 143 2506
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.009
X-RAY DIFFRACTIONx_angle_deg2.09
Refinement
*PLUS
Solvent computation
*PLUS
Displacement parameters
*PLUS

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