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Yorodumi- PDB-1c5l: STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING,... -
+Open data
-Basic information
Entry | Database: PDB / ID: 1c5l | |||||||||
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Title | STRUCTURAL BASIS FOR SELECTIVITY OF A SMALL MOLECULE, S1-BINDING, SUB-MICROMOLAR INHIBITOR OF UROKINASE TYPE PLASMINOGEN ACTIVATOR | |||||||||
Components |
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Keywords | BLOOD CLOTTING/HYDROLASE INHIBITOR / selective / S1 site inhibitor / structure-based drug design / urokinase / trypsin / thrombin / BLOOD CLOTTING-HYDROLASE INHIBITOR COMPLEX | |||||||||
Function / homology | Function and homology information negative regulation of serine-type peptidase activity / 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 ...negative regulation of serine-type peptidase activity / 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 / serine-type endopeptidase inhibitor 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 | |||||||||
Biological species | Homo sapiens (human) Hirudo medicinalis (medicinal leech) | |||||||||
Method | X-RAY DIFFRACTION / DIFFERENCE FOURIER PLUS REFINEMENT / Resolution: 1.47 Å | |||||||||
Authors | Katz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L. | |||||||||
Citation | Journal: Chem.Biol. / Year: 2000 Title: Structural basis for selectivity of a small molecule, S1-binding, submicromolar inhibitor of urokinase-type plasminogen activator. Authors: Katz, B.A. / Mackman, R. / Luong, C. / Radika, K. / Martelli, A. / Sprengeler, P.A. / Wang, J. / Chan, H. / Wong, L. | |||||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 1c5l.cif.gz | 151.8 KB | Display | PDBx/mmCIF format |
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PDB format | pdb1c5l.ent.gz | 120.7 KB | Display | PDB format |
PDBx/mmJSON format | 1c5l.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/c5/1c5l ftp://data.pdbj.org/pub/pdb/validation_reports/c5/1c5l | HTTPS FTP |
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-Related structure data
Related structure data | 1c5mC 1c5nC 1c5oC 1c5pC 1c5qC 1c5rC 1c5sC 1c5tC 1c5uC 1c5vC 1c5wC 1c5xC 1c5yC 1c5zC C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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-Components
-Protein/peptide , 2 types, 2 molecules LI
#1: Protein/peptide | Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin |
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#3: Protein/peptide | Mass: 1363.399 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28504, UniProt: P01050*PLUS |
-Protein , 1 types, 1 molecules H
#2: Protein | Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin |
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-Non-polymers , 3 types, 295 molecules
#4: Chemical | ChemComp-NA / |
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#5: Chemical | ChemComp-CA / |
#6: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 2 |
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-Sample preparation
Crystal | Density Matthews: 2.74 Å3/Da / Density % sol: 36.7 % | |||||||||||||||||||||||||||||||||||
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Crystal grow | Method: vapor diffusion / pH: 8.2 Details: Thrombin was purchased from Haematologic Technologies, Inc. and acetyl-hirudin from Bachem. Thrombin was prepared as described (Skrzpczak-Jankun et al., 1991). Thrombin (1.0 mg/ml in 50 mM ...Details: Thrombin was purchased from Haematologic Technologies, Inc. and acetyl-hirudin from Bachem. Thrombin was prepared as described (Skrzpczak-Jankun et al., 1991). Thrombin (1.0 mg/ml in 50 mM HEPES, 50 % glycerol, pH 7.0) was incubated with 1.0 mM acetyl-hirudin for 1 hr at 4 deg C. Glycerol was removed and the complex concentrated with a centricon 10 (Amicon) to about 10 mg/ml as determined by the Biorad protein assay kit using bovine serum albumin. Crystals of thrombin-acetyl-hirudin were grown in hanging drops by vapor diffusion after streak seeding. The drops were made from 5 microliters of complex and 5 microliters of reservoir solution (0.10 M Tris, 0.50 M NaCl, 22 % (by volume) PEG 4K, pH 8.20)., VAPOR DIFFUSION | |||||||||||||||||||||||||||||||||||
Crystal grow | *PLUS pH: 7.5 / Method: vapor diffusion, hanging drop / Details: used seeding | |||||||||||||||||||||||||||||||||||
Components of the solutions | *PLUS
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-Data collection
Diffraction | Mean temperature: 298 K |
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Diffraction source | Source: ROTATING ANODE / Wavelength: 1.5418 |
Detector | Type: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Apr 8, 1999 / Details: MSC MIRRORS |
Radiation | Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.5418 Å / Relative weight: 1 |
Reflection | Resolution: 1.31→44.16 Å / Num. all: 51674 / % possible obs: 69 % / Observed criterion σ(I): 0.8 / Redundancy: 2.2 % / Rmerge(I) obs: 0.071 / Net I/σ(I): 9.8 |
Reflection shell | Resolution: 1.47→1.54 Å / Rmerge(I) obs: 0.371 / Mean I/σ(I) obs: 1.3 / % possible all: 35.8 |
-Processing
Software |
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Refinement | Method to determine structure: DIFFERENCE FOURIER PLUS REFINEMENT Resolution: 1.47→7.5 Å / Cross valid method: X-PLOR / σ(F): 1.8 Details: Met_H84, Met_H106, Met_H210, Glu_H97A, Glu_H217, Lys_H224, Ser_H27, and Glu_H192 were simultaneously refined in two conformations. No density was observed for Trp148, Thr149, Ala149A, ...Details: Met_H84, Met_H106, Met_H210, Glu_H97A, Glu_H217, Lys_H224, Ser_H27, and Glu_H192 were simultaneously refined in two conformations. No density was observed for Trp148, Thr149, Ala149A, Asn149B, Val149C, Gly149D, and Lys149E in the autolysis loop, and these residues are not included in the model. Disordered waters include: HOH395 which is in a special position; HOH396 is close to a symmetry related equivalent of itself; HOH422 which is close to HOH432; HOH434 is close to a symmetry related equivalent of itself; HOH447 which is close to HOH494; (THE ABOVE WATERS HAVE VERY STRONG DENSITY AND THEIR REFINED OCCUPANCIES ARE SIGNIFICANTLY GREATER THAN UNITY. THEY MAY REFLECT A DIFFERENT STRUCTURAL FEATURE THAN DISORDERED WATERS). HOH495 which is close to HOH499; HOH504 which is close to HOH506; HOH578 which is close to a symmetry-related equivalent of HOH579; HOH580 WHICH IS CLOSE TO HOH578 AND TO A SYMMETRY-RELATED EQUIVALENT OF HOH579; HOH652 WHICH IS CLOSE TO HOH759; HOH687 WHICH IS CLOSE TO HOH688; HOH717 WHICH IS CLOSE TO THE SIDE CHAIN OF LYS_H145; HOH733 WHICH IS CLOSE TO THE SIDE CHAIN OF SER_L1E; HOH786 IS CLOSE TO A SYMMETRY RELATED EQUIVALENT OF ITSELF. HIS_H57 IS MONOPROTONATED ON THE DELTA NITROGEN. HIS_H91 AND HIS_ H119 ARE MONOPROTONATED ON THE EPSILON NITROGEN.
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Refinement step | Cycle: LAST / Resolution: 1.47→7.5 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.47→1.54 Å / Total num. of bins used: 8
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Xplor file |
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Software | *PLUS Name: X-PLOR / Version: 3.1 / Classification: refinement | |||||||||||||||||||||||||||
Refinement | *PLUS Lowest resolution: 7.5 Å / σ(F): 1.8 / % reflection Rfree: 10 % / Rfactor obs: 0.217 | |||||||||||||||||||||||||||
Solvent computation | *PLUS | |||||||||||||||||||||||||||
Displacement parameters | *PLUS | |||||||||||||||||||||||||||
Refine LS restraints | *PLUS
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LS refinement shell | *PLUS Rfactor Rfree: 0.532 / Rfactor Rwork: 0.527 |