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- PDB-1ghw: A NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTER... -

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Basic information

Entry
Database: PDB / ID: 1ghw
TitleA NOVEL SERINE PROTEASE INHIBITION MOTIF INVOLVING A MULTI-CENTERED SHORT HYDROGEN BONDING NETWORK AT THE ACTIVE SITE
Components
  • (THROMBIN) x 2
  • ACETYL HIRUDIN
KeywordsHYDROLASE/HYDROLASE INHIBITOR / three-centered / very short hydrogen bond / oxyanion hole water / shift of pKa of His57 / structure-based drug design / specificity / urokinase / trypsin / thrombin / Zn+2-mediated inhibition / BLOOD CLOTTING / 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 / 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-BMZ / Prothrombin / Hirudin-2
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / Resolution: 1.75 Å
AuthorsKatz, B.A. / Elrod, K. / Luong, C. / Rice, M. / Mackman, R.L. / Sprengeler, P.A. / Spencer, J. / Hatayte, J. / Janc, J. / Link, J. ...Katz, B.A. / Elrod, K. / Luong, C. / Rice, M. / Mackman, R.L. / Sprengeler, P.A. / Spencer, J. / Hatayte, J. / Janc, J. / Link, J. / Litvak, J. / Rai, R. / Rice, K. / Sideris, S. / Verner, E. / Young, W.
CitationJournal: J.Mol.Biol. / Year: 2001
Title: A novel serine protease inhibition motif involving a multi-centered short hydrogen bonding network at the active site
Authors: Katz, B.A. / Elrod, K. / Luong, C. / Rice, M.J. / Mackman, R.L. / Sprengeler, P.A. / Spencer, J. / Hataye, J. / Janc, J. / Link, J. / Litvak, J. / Rai, R. / Rice, K. / Sideris, S. / Verner, E. / Young, W.
History
DepositionJan 22, 2001Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 22, 2002Provider: repository / Type: Initial release
Revision 1.1Oct 21, 2007Group: 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 1.5Oct 4, 2017Group: Refinement description / Category: software
Revision 1.6Dec 27, 2023Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_conn_angle / struct_conn / struct_conn_type / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._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.conn_type_id / _struct_conn.id / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_conn_type.id / _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: THROMBIN
H: THROMBIN
I: ACETYL HIRUDIN
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,4585
Polymers35,1823
Non-polymers2762
Water6,900383
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.890, 72.220, 72.740
Angle α, β, γ (deg.)90.00, 100.97, 90.00
Int Tables number5
Space group name H-MC121
Components on special symmetry positions
IDModelComponents
11H-395-

HOH

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide THROMBIN / 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 ACETYL HIRUDIN


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

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Protein , 1 types, 1 molecules H

#2: Protein THROMBIN / E.C.3.4.21.5 / COAGULATION FACTOR II


Mass: 29594.055 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 , 3 types, 385 molecules

#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-BMZ / 2-(2-HYDROXY-PHENYL)-1H-BENZOIMIDAZOLE-5-CARBOXAMIDINE


Mass: 253.279 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H13N4O
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 383 / 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: 2.63 Å3/Da / Density % sol: 53.29 %
Crystal growTemperature: 298 K / Method: vapor diffusion / pH: 7.3
Details: PEG 4000, NaCl, pH 7.3, vapor diffusion, temperature 298K
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop / PH range low: 8.2 / PH range high: 7.5
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetailsChemical formula
110 mg/mlprotein1drop
20.10 MHEPES1reservoirpH7.5 or 8.2
30.30 M1reservoirNaCl
422 %(v/v)PEG5000 MME1reservoir

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RU200 / Wavelength: 1.5418
DetectorType: SIEMENS / Detector: AREA DETECTOR / Date: Jun 12, 1996
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.75→50 Å / Num. obs: 26726 / Observed criterion σ(I): 1 / Redundancy: 2.1 % / Rmerge(I) obs: 0.085 / Net I/σ(I): 10.1
Reflection shellResolution: 1.75→1.83 Å / Rmerge(I) obs: 0.259 / Num. unique all: 1252 / % possible all: 29.4
Reflection
*PLUS
Highest resolution: 1.65 Å / Num. obs: 28777 / Redundancy: 2.1 % / Num. measured all: 59250

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Processing

Software
NameVersionClassification
SADIEdata collection
SADIEdata reduction
SAINTdata reduction
X-PLOR3.851refinement
SADIEdata scaling
SAINTdata scaling
RefinementResolution: 1.75→7 Å / σ(F): 1.8 / Stereochemistry target values: X-PLOR force field
Details: Lys_H60F, Met_H84, Leu_H130, and Val_H157 were simultaneously refined in two conformations. His_H119 was placed into two cnformations. No density was observed for Trp148, Thr149, Ala149A, ...Details: Lys_H60F, Met_H84, Leu_H130, and Val_H157 were simultaneously refined in two conformations. His_H119 was placed into two cnformations. 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. No dennsity was observed for C-terminal residues of the heavy chain following Phe_H245. Residues after Phe_H245 are not included in the model. HOH477 makes a short hydrogen bond with OgSer195 and with O6' of the inhibitor Disordered waters include: HOH395 which is in a special position. (It is close to a symmetry related equivalent of itself); HOH396 is close to a symmetry related equivalent of itself; HOH397 is close to a symmetry related equivalent of itself. The above three "waters" correspond to density that is more electron dense than waters. The occupancies were allowed to refine to values greater than unity. HOH859 which H-bonds with His_H119 in conformation 1; HOH424 which H-bonds with His_H119 in conformation 2; HOH504 which is close to HOH505; HOH1122 which is close to HOH1123; HOH700 which is close to HOH701. HIS_H57 IS doubly protonated. HIS_H91 and His_H119 are MONOPROTONATED ON the epsilon nitrogen
RfactorNum. reflection% reflection
Rfree0.234 2280 -
Rwork0.196 --
obs0.198 23179 63.6 %
Refinement stepCycle: LAST / Resolution: 1.75→7 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2417 0 20 383 2820
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_bond_d0.019
X-RAY DIFFRACTIONx_angle_deg3.7
Software
*PLUS
Name: X-PLOR / Version: 3.851 / Classification: refinement
Refinement
*PLUS
Lowest resolution: 7 Å / σ(F): 1.75 / % reflection Rfree: 10 % / Rfactor all: 0.198 / Rfactor obs: 0.196
Solvent computation
*PLUS
Displacement parameters
*PLUS
Refine LS restraints
*PLUS
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONx_angle_deg3.7
X-RAY DIFFRACTIONx_dihedral_angle_d
X-RAY DIFFRACTIONx_dihedral_angle_deg25.3
LS refinement shell
*PLUS
Highest resolution: 1.75 Å / Lowest resolution: 1.83 Å / Rfactor Rfree: 0.234 / Rfactor obs: 0.199

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