[English] 日本語
Yorodumi
- PDB-4ux6: The discovery of novel, potent and highly selective inhibitors of... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 4ux6
TitleThe discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS)
Components(NITRIC OXIDE SYNTHASE, INDUCIBLE) x 2
KeywordsOXIDOREDUCTASE / DRUG DESIGN
Function / homology
Function and homology information


Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / Peroxisomal protein import / cAMP-dependent protein kinase regulator activity / prostaglandin secretion / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton ...Nitric oxide stimulates guanylate cyclase / ROS and RNS production in phagocytes / G protein-coupled receptor signaling pathway coupled to cGMP nucleotide second messenger / Peroxisomal protein import / cAMP-dependent protein kinase regulator activity / prostaglandin secretion / positive regulation of killing of cells of another organism / tetrahydrobiopterin binding / arginine binding / cortical cytoskeleton / superoxide metabolic process / cGMP-mediated signaling / nitric-oxide synthase binding / cellular response to cytokine stimulus / regulation of cytokine production involved in inflammatory response / peptidyl-cysteine S-nitrosylation / regulation of insulin secretion / cellular response to organic cyclic compound / nitric-oxide synthase (NADPH) / blood vessel remodeling / response to tumor necrosis factor / nitric-oxide synthase activity / nitric oxide mediated signal transduction / arginine catabolic process / negative regulation of blood pressure / nitric oxide biosynthetic process / response to hormone / positive regulation of interleukin-8 production / response to bacterium / Hsp90 protein binding / negative regulation of protein catabolic process / beta-catenin binding / regulation of blood pressure / peroxisome / positive regulation of interleukin-6 production / cellular response to type II interferon / circadian rhythm / cellular response to xenobiotic stimulus / FMN binding / flavin adenine dinucleotide binding / NADP binding / actin binding / regulation of cell population proliferation / cellular response to lipopolysaccharide / response to lipopolysaccharide / response to hypoxia / calmodulin binding / intracellular signal transduction / defense response to bacterium / cadherin binding / inflammatory response / positive regulation of apoptotic process / negative regulation of gene expression / heme binding / protein kinase binding / perinuclear region of cytoplasm / protein homodimerization activity / extracellular space / identical protein binding / metal ion binding / nucleus / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily ...Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding / NADPH-cytochrome p450 reductase, FAD-binding, alpha-helical domain superfamily / FAD binding domain / Flavodoxin-like / Flavoprotein pyridine nucleotide cytochrome reductase / Flavodoxin / Flavodoxin-like domain profile. / Flavodoxin/nitric oxide synthase / Oxidoreductase FAD/NAD(P)-binding / Oxidoreductase NAD-binding domain / FAD-binding domain, ferredoxin reductase-type / Ferredoxin-NADP reductase (FNR), nucleotide-binding domain / Ferredoxin reductase-type FAD binding domain profile. / Riboflavin synthase-like beta-barrel / Flavoprotein-like superfamily
Similarity search - Domain/homology
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / O-(5-methyl-2-nitrophenyl)-D-tyrosinamide / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 3 Å
AuthorsCheshire, D.R. / Andrews, G. / Beaton, H.G. / Birkinshaw, T. / Boughton-Smith, N. / Connolly, S. / Cook, T.R. / Cooper, A. / Cooper, S.L. / Cox, D. ...Cheshire, D.R. / Andrews, G. / Beaton, H.G. / Birkinshaw, T. / Boughton-Smith, N. / Connolly, S. / Cook, T.R. / Cooper, A. / Cooper, S.L. / Cox, D. / Dixon, J. / Gensmantel, N. / Hamley, P.J. / Harrison, R. / Hartopp, P. / Kack, H. / Luker, T. / Mete, A. / Millichip, I. / Nicholls, D.J. / Pimm, A.D. / St-Gallay, S.A. / Wallace, A.V.
Citation
Journal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: The Discovery of Novel, Potent and Highly Selective Inhibitors of Inducible Nitric Oxide Synthase (Inos).
Authors: Cheshire, D.R. / Aberg, A. / Andersson, G.M.K. / Andrews, G. / Beaton, H.G. / Birkinshaw, T.N. / Boughton-Smith, N. / Connolly, S. / Cook, T.R. / Cooper, A. / Cooper, S.L. / Cox, D. / Dixon, ...Authors: Cheshire, D.R. / Aberg, A. / Andersson, G.M.K. / Andrews, G. / Beaton, H.G. / Birkinshaw, T.N. / Boughton-Smith, N. / Connolly, S. / Cook, T.R. / Cooper, A. / Cooper, S.L. / Cox, D. / Dixon, J. / Gensmantel, N. / Hamley, P.J. / Harrison, R. / Hartopp, P. / Kack, H. / Leeson, P.D. / Luker, T. / Mete, A. / Millichip, I. / Nicholls, D.J. / Pimm, A.D. / St-Gallay, S.A. / Wallace, A.V.
#1: Journal: Handbook of Medicinal Chemis / Year: 2014
Title: Structure-Based Design for Medicinal Chemists
Authors: Davis, A.M. / Blaney, J.
History
DepositionAug 19, 2014Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 8, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 15, 2014Group: Database references
Revision 1.2Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: NITRIC OXIDE SYNTHASE, INDUCIBLE
B: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)49,0055
Polymers47,8322
Non-polymers1,1733
Water0
1
A: NITRIC OXIDE SYNTHASE, INDUCIBLE
B: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules

A: NITRIC OXIDE SYNTHASE, INDUCIBLE
B: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)98,01110
Polymers95,6654
Non-polymers2,3466
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation7_555y,x,-z+1/31
Buried area11400 Å2
ΔGint-89.7 kcal/mol
Surface area33230 Å2
MethodPISA
Unit cell
Length a, b, c (Å)213.550, 213.550, 115.990
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

-
Components

#1: Protein/peptide NITRIC OXIDE SYNTHASE, INDUCIBLE / / INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / MACROPHAGE NOS / MAC-NOS / NOS TYPE II / PEPTIDYL- ...INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / MACROPHAGE NOS / MAC-NOS / NOS TYPE II / PEPTIDYL-CYSTEINE S-NITROSYLASE NOS2 / INDUCIBLE NITRIC OXIDE SYNTHASE


Mass: 2797.133 Da / Num. of mol.: 1 / Fragment: OXYGENASE DOMAIN, UNP RESIDUES 77-100
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P29477, nitric-oxide synthase (NADPH)
#2: Protein NITRIC OXIDE SYNTHASE, INDUCIBLE / / INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / MACROPHAGE NOS / MAC-NOS / NOS TYPE II / PEPTIDYL- ...INDUCIBLE NO SYNTHASE / INDUCIBLE NOS / INOS / MACROPHAGE NOS / MAC-NOS / NOS TYPE II / PEPTIDYL-CYSTEINE S-NITROSYLASE NOS2 / INDUCIBLE NITRIC OXIDE SYNTHASE


Mass: 45035.242 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 108-496
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P29477, nitric-oxide synthase (NADPH)
#3: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#4: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#5: Chemical ChemComp-YWO / O-(5-methyl-2-nitrophenyl)-D-tyrosinamide


Mass: 315.324 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H17N3O4

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDescription: NONE
Crystal growpH: 6.4 / Details: pH 6.4

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: MAX II / Beamline: I711 / Wavelength: 0.97
DetectorType: BRUKER / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 3→20 Å / Num. obs: 10438 / % possible obs: 95 % / Observed criterion σ(I): 2 / Redundancy: 6 % / Rmerge(I) obs: 0.1 / Net I/σ(I): 12

-
Processing

Software
NameClassification
CNSrefinement
MOSFLMdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 3→20 Å / Cross valid method: THROUGHOUT / σ(F): 2
Details: THIS IS A STRUCTURE SOLVED MANY YEARS AGO AS SUCH THERE ARE NO EXPERIMENTAL DATA SUPPORTING THE MODEL.
RfactorNum. reflection% reflection
Rwork0.23 --
obs0.23 3097 95 %
Refinement stepCycle: LAST / Resolution: 3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3368 0 83 0 3451
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_bond_d0.01
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.9
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it
X-RAY DIFFRACTIONc_mcangle_it
X-RAY DIFFRACTIONc_scbond_it
X-RAY DIFFRACTIONc_scangle_it

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more