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- PDB-1o5g: Dissecting and Designing Inhibitor Selectivity Determinants at th... -

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Basic information

Entry
Database: PDB / ID: 1o5g
TitleDissecting and Designing Inhibitor Selectivity Determinants at the S1 site Using an Artificial Ala190 Protease (Ala190 uPA)
Components
  • (Prothrombin) x 2
  • Hirudin IIIB'
KeywordsBLOOD CLOTTING / HYDROLASE/INHIBITOR / Ala190 uPA / S1 site / selectivity / conserved water displacement hydrogen bond deficit / trypsin / thrombin / hepsin / factor VIIa / hydrolase / HYDROLASE-HYDROLASE INHIBITOR COMPLEX / 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 / regulation of blood coagulation / neutrophil-mediated killing of gram-negative bacterium / 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 / 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 / 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 / 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 / positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction / cell surface receptor signaling pathway / blood microparticle / positive regulation of protein phosphorylation / G protein-coupled receptor signaling pathway / endoplasmic reticulum lumen / serine-type endopeptidase activity / signaling receptor binding / 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. / 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
Chem-CR9 / Prothrombin / Hirudin-2 / Hirudin-3B'
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.75 Å
AuthorsKatz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. ...Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
CitationJournal: J.Mol.Biol. / Year: 2004
Title: Dissecting and designing inhibitor selectivity determinants at the S1 site using an artificial Ala190 protease (Ala190 uPA).
Authors: Katz, B.A. / Luong, C. / Ho, J.D. / Somoza, J.R. / Gjerstad, E. / Tang, J. / Williams, S.R. / Verner, E. / Mackman, R.L. / Young, W.B. / Sprengeler, P.A. / Chan, H. / Mortara, K. / Janc, J.W. / McGrath, M.E.
History
DepositionSep 9, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 21, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 26, 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 1.4Mar 13, 2013Group: Other
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_ref_seq_dif / struct_site
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr2_auth_seq_id / _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

Downloads & links

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Assembly

Deposited unit
L: Prothrombin
H: Prothrombin
I: Hirudin IIIB'
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8146
Polymers35,3683
Non-polymers4453
Water2,126118
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5050 Å2
ΔGint-30 kcal/mol
Surface area12740 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.34, 72.04, 72.95
Angle α, β, γ (deg.)90.0, 100.83, 90.0
Int Tables number5
Cell settingmonoclinic
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-394-

HOH

21H-395-

HOH

31H-396-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

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


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: LIGHT CHAIN, RESIDUES 328-363 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide Hirudin IIIB'


Mass: 1491.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28511, UniProt: P28504*PLUS

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Protein , 1 types, 1 molecules H

#2: Protein Prothrombin / E.C.3.4.21.5 / Coagulation factor II


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: HEAVY CHAIN, RESIDUES 364-620 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin

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Non-polymers , 4 types, 121 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca
#6: Chemical ChemComp-CR9 / 2-{5-[AMINO(IMINIO)METHYL]-6-FLUORO-1H-BENZIMIDAZOL-2-YL}-6-[(2-METHYLCYCLOHEXYL)OXY]BENZENOLATE / CRA_11092


Mass: 382.431 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H23FN4O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 118 / 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: 2.6 Å3/Da / Density % sol: 52.72 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.5
Details: 2-propanol, PEG 4000, pH 6.5, vapor diffusion at 298 K, pH 7.50

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Data collection

DiffractionMean temperature: 285 K / Ambient temp details: Crystal Cooler
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: May 22, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.75→27.69 Å / Num. all: 36636 / Num. obs: 35940 / % possible obs: 98.1 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.068 / Net I/σ(I): 7.1
Reflection shellResolution: 1.75→1.83 Å / % possible obs: 39.06 % / Rmerge(I) obs: 0.418 / Mean I/σ(I) obs: 1 / Num. unique all: 4480

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Processing

Software
NameVersionClassification
CrystalClear1.3data collection
CrystalClear1.3data reduction
X-PLOR3.851refinement
CrystalClear(MSC/RIGAKU)data scaling
Quantamodel building
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.75→7 Å / Cross valid method: THROUGHOUT / σ(F): 1.1 / Stereochemistry target values: X-PLOR force field
Details: Asp_H21, Met_H84, His_H119, Val_H157 were simultaneously refined in two conformations. Residues after Ile_L16K (light chain) have weak or no density, and are not included in the model. ...Details: Asp_H21, Met_H84, His_H119, Val_H157 were simultaneously refined in two conformations. Residues after Ile_L16K (light chain) have weak or no density, and are not included in the model. Density is absent for the last two residues of the heavy chain, which are not included in the model. No density was observed for Thr147, Trp148, Thr149, Ala149A, Asn149B, Val149C, Gly149D, and Lys149E in the autolysis loop, and these residues are not included in the model. In the non-active site peptide inhibitor (acetylhirudin) the tyrosine hydroxyl is sulfonated. HOH477, OgSer195 and O6' and N3 of the inhibitor make a 3-centered short hydrogen bond array. Disordered waters include: HOH_395 is close to a symmetry related equivalent of itself. AHOH_393 is close to BHOH_393. AHOH_394 is close to a symmetry related equivalent of itself. BHOH_395 is close to a symmetry related equivalent of itself. HOH_393, HOH_394, and HOH_395 form a cluster of density Density for these "waters" is greater than for real waters, so occupancies were refined. AHOH_674 is close to BHOH_674.
RfactorNum. reflection% reflection
Rfree0.238 2688 10 %
Rwork0.208 --
obs0.21 26771 74.29 %
all-36036 -
Refinement stepCycle: LAST / Resolution: 1.75→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2392 0 30 118 2540
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.018
X-RAY DIFFRACTIONx_angle_deg3.6

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