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- PDB-4ux6: The discovery of novel, potent and highly selective inhibitors of... -

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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 / positive regulation of killing of cells of another organism / prostaglandin secretion / tetrahydrobiopterin binding / arginine binding / cGMP-mediated signaling ...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 / positive regulation of killing of cells of another organism / prostaglandin secretion / tetrahydrobiopterin binding / arginine binding / cGMP-mediated signaling / superoxide metabolic process / cortical cytoskeleton / nitric-oxide synthase binding / peptidyl-cysteine S-nitrosylation / cellular response to cytokine stimulus / regulation of cytokine production involved in inflammatory response / cellular response to organic cyclic compound / blood vessel remodeling / nitric-oxide synthase (NADPH) / nitric oxide mediated signal transduction / response to tumor necrosis factor / nitric-oxide synthase activity / arginine catabolic process / nitric oxide biosynthetic process / negative regulation of blood pressure / regulation of insulin secretion / response to hormone / positive regulation of interleukin-8 production / response to bacterium / Hsp90 protein binding / negative regulation of protein catabolic process / cellular response to type II interferon / beta-catenin binding / regulation of blood pressure / positive regulation of interleukin-6 production / circadian rhythm / cellular response to xenobiotic stimulus / peroxisome / FMN binding / flavin adenine dinucleotide binding / NADP binding / regulation of cell population proliferation / actin binding / cellular response to lipopolysaccharide / response to lipopolysaccharide / response to hypoxia / calmodulin binding / intracellular signal transduction / defense response to bacterium / inflammatory response / cadherin binding / 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 / nucleus / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
Nitric-oxide synthase, eukaryote / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily / : / Nitric oxide synthase, oxygenase domain / Nitric oxide synthase (NOS) signature. / Sulfite reductase [NADPH] flavoprotein alpha-component-like, FAD-binding ...Nitric-oxide synthase, eukaryote / Nitric oxide synthase, N-terminal / Nitric oxide synthase, N-terminal domain superfamily / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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
Water00
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

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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


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

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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

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

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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

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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

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