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- PDB-1no9: Design of weakly basic thrombin inhibitors incorporating novel P1... -

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Basic information

Entry
Database: PDB / ID: 1no9
TitleDesign of weakly basic thrombin inhibitors incorporating novel P1 binding functions: molecular and X-ray crystallographic studies.
Components
  • (Alpha Thrombin) x 2
  • hirugen
KeywordsHYDROLASE/HYDROLASE INHIBITOR / COMPLEX (SERINE PROTEASE-INHIBITOR) / BLOOD COAGULATION / SERINE PROTEINASE INHIBITION / N / N-DIPHENYLCARBAMOYL-AMINOGUANIDINE / HYDROLASE / HYDROLASE-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
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
N4-(N,N-DIPHENYLCARBAMOYL)-AMINOGUANIDINE / Prothrombin / Hirudin variant-1 / Hirudin variant-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Hirudo medicinalis (medicinal leech)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.9 Å
AuthorsDe Simone, G. / Menchise, V. / Omaggio, S. / Pedone, C. / Scozzafava, A. / Supuran, C.T.
CitationJournal: Biochemistry / Year: 2003
Title: DESIGN OF WEAKLY BASIC THROMBIN INHIBITORS INCORPORATING NOVEL P1 BINDING FUNCTIONS: MOLECULAR AND X-RAY CRYSTALLOGRAPHIC STUDIES
Authors: De Simone, G. / Menchise, V. / Omaggio, S. / Pedone, C. / Scozzafava, A. / Supuran, C.T.
History
DepositionJan 16, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 26, 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 1.3Jul 29, 2020Group: Advisory / Data collection ...Advisory / Data collection / Derived calculations / Structure summary
Category: chem_comp / entity ...chem_comp / entity / pdbx_chem_comp_identifier / pdbx_entity_nonpoly / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues / struct_conn / struct_site / struct_site_gen
Item: _chem_comp.name / _chem_comp.type ..._chem_comp.name / _chem_comp.type / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _struct_conn.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.pdbx_ptnr1_PDB_ins_code / _struct_conn.pdbx_role / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_comp_id
Description: Carbohydrate remediation / Provider: repository / Type: Remediation
Revision 1.4Aug 16, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms / pdbx_unobs_or_zero_occ_residues
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.5Nov 15, 2023Group: Data collection / Category: chem_comp_atom / chem_comp_bond / Item: _chem_comp_atom.atom_id / _chem_comp_bond.atom_id_2

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
L: Alpha Thrombin
H: Alpha Thrombin
I: hirugen
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,8595
Polymers35,3683
Non-polymers4912
Water2,648147
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4810 Å2
ΔGint-11 kcal/mol
Surface area13900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.413, 72.192, 72.705
Angle α, β, γ (deg.)90.00, 100.57, 90.00
Int Tables number5
Space group name H-MC121

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Components

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Protein/peptide , 2 types, 2 molecules LI

#1: Protein/peptide Alpha Thrombin


Mass: 4096.534 Da / Num. of mol.: 1 / Fragment: Light Chain / Source method: isolated from a natural source / Details: PLASMA / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#3: Protein/peptide hirugen / N-ACETYLHIRUDIN 53 - 64 WITH SULFATO-TYR 63 / Hirudin I Fragments


Mass: 1491.528 Da / Num. of mol.: 1 / Fragment: Chain I / Source method: obtained synthetically / Source: (synth.) Hirudo medicinalis (medicinal leech) / References: UniProt: P28501, UniProt: P01050*PLUS

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Protein / Sugars , 2 types, 2 molecules H

#2: Protein Alpha Thrombin


Mass: 29780.219 Da / Num. of mol.: 1 / Fragment: Heavy Chain / Source method: isolated from a natural source / Details: PLASMA / Source: (natural) Homo sapiens (human) / References: UniProt: P00734, thrombin
#4: Sugar ChemComp-NAG / 2-acetamido-2-deoxy-beta-D-glucopyranose / N-acetyl-beta-D-glucosamine / 2-acetamido-2-deoxy-beta-D-glucose / 2-acetamido-2-deoxy-D-glucose / 2-acetamido-2-deoxy-glucose / N-ACETYL-D-GLUCOSAMINE / N-Acetylglucosamine


Type: D-saccharide, beta linking / Mass: 221.208 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Formula: C8H15NO6
IdentifierTypeProgram
DGlcpNAcbCONDENSED IUPAC CARBOHYDRATE SYMBOLGMML 1.0
N-acetyl-b-D-glucopyranosamineCOMMON NAMEGMML 1.0
b-D-GlcpNAcIUPAC CARBOHYDRATE SYMBOLPDB-CARE 1.0
GlcNAcSNFG CARBOHYDRATE SYMBOLGMML 1.0

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Non-polymers , 2 types, 148 molecules

#5: Chemical ChemComp-4ND / N4-(N,N-DIPHENYLCARBAMOYL)-AMINOGUANIDINE


Mass: 269.302 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H15N5O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 147 / 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: 2.51 Å3/Da / Density % sol: 50.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: PEG 4000, Sodium Chloride, pH 7.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS / Wavelength: 1.5418 Å
DetectorType: ENRAF-NONIUS / Detector: AREA DETECTOR / Date: Jan 15, 2002 / Details: mirrors
RadiationMonochromator: mirrors / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→20 Å / Num. all: 28435 / Num. obs: 28435 / % possible obs: 98.5 % / Observed criterion σ(F): 0 / Rsym value: 0.052 / Net I/σ(I): 16.3
Reflection shellResolution: 1.9→1.97 Å / Mean I/σ(I) obs: 3.4 / Num. unique all: 2767 / Rsym value: 0.247 / % possible all: 96.2
Reflection
*PLUS
Lowest resolution: 20 Å / Num. measured all: 125775 / Rmerge(I) obs: 0.052
Reflection shell
*PLUS
% possible obs: 96.2 % / Rmerge(I) obs: 0.247

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Processing

Software
NameClassification
DENZOdata reduction
SCALEPACKdata scaling
CNSrefinement
CNSphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: PDB ENTRY 1HAH

1hah


Resolution: 1.9→20 Å / Isotropic thermal model: isotropic / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.204 2709 -RANDOM
Rwork0.183 ---
all-28435 --
obs-27300 95.3 %-
Displacement parametersBiso mean: 32.19 Å2
Refinement stepCycle: LAST / Resolution: 1.9→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2444 0 29 147 2620
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_angle_deg1.53
LS refinement shellResolution: 1.9→20 Å
RfactorNum. reflection% reflection
Rfree0.183 2709 -
Rwork0.204 --
obs-27300 95.3 %
Refinement
*PLUS
Lowest resolution: 20 Å / % reflection Rfree: 10 %
Solvent computation
*PLUS
Displacement parameters
*PLUS

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