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- PDB-1sl3: crystal structue of Thrombin in complex with a potent P1 heterocy... -

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Basic information

Entry
Database: PDB / ID: 1sl3
Titlecrystal structue of Thrombin in complex with a potent P1 heterocycle-Aryl based inhibitor
Components
  • Hirudin
  • thrombin
KeywordsBLOOD CLOTTING / HYDROLASE/INHIBITOR / thrombin inhibitor complex / HYDROLASE-INHIBITOR COMPLEX
Function / homology
Function and homology information


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-activated receptor signaling pathway / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / Defective F8 cleavage by thrombin / ligand-gated ion channel signaling pathway ...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-activated receptor signaling pathway / thrombin / neutrophil-mediated killing of gram-negative bacterium / regulation of blood coagulation / Defective F8 cleavage by thrombin / ligand-gated ion channel signaling pathway / Platelet Aggregation (Plug Formation) / negative regulation of astrocyte differentiation / positive regulation of collagen biosynthetic process / negative regulation of platelet activation / negative regulation of blood coagulation / positive regulation of blood coagulation / negative regulation of fibrinolysis / regulation of cytosolic calcium ion concentration / Transport of gamma-carboxylated protein precursors from the endoplasmic reticulum to the Golgi apparatus / Gamma-carboxylation of protein precursors / Common Pathway of Fibrin Clot Formation / Removal of aminoterminal propeptides from gamma-carboxylated proteins / fibrinolysis / negative regulation of proteolysis / Intrinsic Pathway of Fibrin Clot Formation / negative regulation of cytokine production involved in inflammatory response / positive regulation of release of sequestered calcium ion into cytosol / Peptide ligand-binding receptors / Regulation of Complement cascade / acute-phase response / positive regulation of receptor signaling pathway via JAK-STAT / Cell surface interactions at the vascular wall / lipopolysaccharide binding / growth factor activity / serine-type endopeptidase inhibitor activity / positive regulation of insulin secretion / platelet activation / positive regulation of protein localization to nucleus / response to wounding / Golgi lumen / antimicrobial humoral immune response mediated by antimicrobial peptide / 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 / heparin binding / regulation of cell shape / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of protein phosphorylation / positive regulation of cell growth / : / G alpha (q) signalling events / blood microparticle / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / receptor ligand activity / endoplasmic reticulum lumen / signaling receptor binding / serine-type endopeptidase activity / 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 / Serine proteases, trypsin family, histidine active site. / Peptidase S1A, chymotrypsin family / 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-170 / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.81 Å
AuthorsYoung, M.B. / Barrow, J.C. / Glass, K.L. / Lundell, G.F. / Newton, C.L. / Pellicore, J.M. / Rittle, K.E. / Selnick, H.G. / Stauffer, K.J. / Vacca, J.P. ...Young, M.B. / Barrow, J.C. / Glass, K.L. / Lundell, G.F. / Newton, C.L. / Pellicore, J.M. / Rittle, K.E. / Selnick, H.G. / Stauffer, K.J. / Vacca, J.P. / Williams, P.D. / Bohn, D. / Clayton, F.C. / Cook, J.J. / Krueger, J.A. / Kuo, L.C. / Lewis, S.D. / Lucas, B.J. / McMasters, D.R. / Miller-Stein, C. / Pietrak, B.L.
CitationJournal: J.Med.Chem. / Year: 2004
Title: Discovery and evaluation of potent P1 aryl heterocycle-based thrombin inhibitors
Authors: Young, M.B. / Barrow, J.C. / Glass, K.L. / Lundell, G.F. / Newton, C.L. / Pellicore, J.M. / Rittle, K.E. / Selnick, H.G. / Stauffer, K.J. / Vacca, J.P. / Williams, P.D. / Bohn, D. / Clayton, ...Authors: Young, M.B. / Barrow, J.C. / Glass, K.L. / Lundell, G.F. / Newton, C.L. / Pellicore, J.M. / Rittle, K.E. / Selnick, H.G. / Stauffer, K.J. / Vacca, J.P. / Williams, P.D. / Bohn, D. / Clayton, F.C. / Cook, J.J. / Krueger, J.A. / Kuo, L.C. / Lewis, S.D. / Lucas, B.J. / McMasters, D.R. / Miller-Stein, C. / Pietrak, B.L.
History
DepositionMar 5, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 3, 2004Provider: 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
Revision 1.4Oct 30, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: thrombin
B: Hirudin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,0673
Polymers34,5142
Non-polymers5521
Water5,062281
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)70.0, 71.5, 72.5
Angle α, β, γ (deg.)90.0, 100.6, 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 / Fragment: alpha-thrombin / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / Organ: PANCREAS / References: UniProt: P00734, thrombin
#2: Protein/peptide Hirudin


Mass: 1434.477 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (natural) Hirudo medicinalis (medicinal leech) / References: UniProt: P28504
#3: Chemical ChemComp-170 / (2-[6-CHLORO-3-{[2,2-DIFLUORO-2-(1-OXIDOPYRIDIN-2-YL)ETHYL]AMINO}-2-OXOPYRAZIN-1(2H)-YL]-N-[5-CHLORO-2-(1H-TETRAZOL-1-YL)BENZYL]ACETAMIDE


Mass: 552.321 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H17Cl2F2N9O3
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 281 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.58 Å3/Da / Density % sol: 52.37 %
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

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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: Sep 12, 2002
RadiationMonochromator: Yale mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.81→50 Å / Num. all: 32335 / Num. obs: 31365 / % possible obs: 97 % / Observed criterion σ(I): 0 / Redundancy: 4 % / Rmerge(I) obs: 0.076 / Rsym value: 0.076
Reflection shellResolution: 1.81→1.87 Å / Rmerge(I) obs: 0.57 / Num. unique all: 3036 / Rsym value: 0.66 / % possible all: 94

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Processing

Software
NameClassification
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.81→50 Å / σ(F): 2 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.24 2890 -random
Rwork0.21 ---
obs0.211 29062 89 %-
all-32335 --
Refinement stepCycle: LAST / Resolution: 1.81→50 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2337 0 37 281 2655
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_angle_d1.46
X-RAY DIFFRACTIONc_mcbond_it1.3641.5
X-RAY DIFFRACTIONc_scbond_it2.1232
X-RAY DIFFRACTIONc_mcangle_it2.0482
X-RAY DIFFRACTIONc_scangle_it3.062.5

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