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- PDB-3nw2: Novel nanomolar Imidazopyridines as selective Nitric Oxide Syntha... -

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Basic information

Entry
Database: PDB / ID: 3nw2
TitleNovel nanomolar Imidazopyridines as selective Nitric Oxide Synthase (iNOS) inhibitors: SAR and structural insights
ComponentsNitric oxide synthase, inducible
KeywordsOXIDOREDUCTASE/OXIDOREDUCTASE inhibitor / CALMODULIN-BINDING / FAD / FMN / IRON / METAL-BINDING / NADP / OXIDOREDUCTASE-OXIDOREDUCTASE inhibitor complex
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 / nitric oxide biosynthetic process / negative regulation of blood pressure / 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 / cellular response to type II interferon / peroxisome / positive regulation of interleukin-6 production / 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
Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / Nitric-oxide synthase, eukaryote / Nitric oxide synthase, domain 2 superfamily / Nitric oxide synthase, domain 1 superfamily / Nitric oxide synthase, domain 3 superfamily ...Bovine Endothelial Nitric Oxide Synthase Heme Domain; Chain: A,domain 3 / Nitric Oxide Synthase; Chain A, domain 3 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase; Chain A, domain 1 / Nitric Oxide Synthase;Heme Domain; Chain A, domain 2 / Nitric Oxide Synthase;Heme Domain;Chain A domain 2 / 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 / Alpha-Beta Complex / Alpha Beta
Similarity search - Domain/homology
5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Chem-MPW / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsGraedler, U. / Fuchss, T. / Ulrich, W.R. / Boer, R. / Strub, A. / Hesslinger, C. / Anezo, C. / Diederichs, K. / Zaliani, A.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2011
Title: Novel nanomolar imidazo[4,5-b]pyridines as selective nitric oxide synthase (iNOS) inhibitors: SAR and structural insights
Authors: Graedler, U. / Fuchss, T. / Ulrich, W.R. / Boer, R. / Strub, A. / Hesslinger, C. / Anezo, C. / Diederichs, K. / Zaliani, A.
History
DepositionJul 9, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Jun 22, 2011Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Dec 21, 2011Group: Database references
Revision 1.3Nov 8, 2017Group: Refinement description / Category: software
Revision 1.4Nov 1, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_source / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _diffrn_source.pdbx_synchrotron_site / _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

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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)100,3179
Polymers97,9972
Non-polymers2,3207
Water1,51384
1
A: Nitric oxide synthase, inducible
hetero molecules

A: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,41410
Polymers97,9972
Non-polymers2,4168
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_655-x+y+1,y,-z+1/21
Buried area6570 Å2
ΔGint-41 kcal/mol
Surface area35680 Å2
MethodPISA
2
B: Nitric oxide synthase, inducible
hetero molecules

B: Nitric oxide synthase, inducible
hetero molecules


Theoretical massNumber of molelcules
Total (without water)100,2218
Polymers97,9972
Non-polymers2,2246
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation9_766-x+2,-x+y+1,-z+5/31
Buried area6360 Å2
ΔGint-37 kcal/mol
Surface area35240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)212.600, 212.600, 111.500
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein Nitric oxide synthase, inducible / / Inducible NO synthase / Inducible NOS / iNOS / NOS type II / Macrophage NOS / MAC-NOS


Mass: 48998.691 Da / Num. of mol.: 2 / Fragment: RESIDUES 77-499
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)

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Non-polymers , 5 types, 91 molecules

#2: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#3: Chemical ChemComp-H4B / 5,6,7,8-TETRAHYDROBIOPTERIN / Tetrahydrobiopterin


Mass: 241.247 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C9H15N5O3 / Comment: neurotransmitter*YM
#4: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#5: Chemical ChemComp-MPW / 2-[2-(4-methoxypyridin-2-yl)ethyl]-3H-imidazo[4,5-b]pyridine


Mass: 254.287 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H14N4O
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 84 / 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: 2

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Sample preparation

CrystalDensity Matthews: 3.71 Å3/Da / Density % sol: 66.86 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 1M ammonium sulfate, 33.3mM Mes buffer pH 6.0, 6.7mM DTT, 6.7mM BH4, 5% beta-octyl glycoside, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: EMBL/DESY, HAMBURG / Beamline: X13 / Wavelength: 0.8017 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Aug 1, 2001
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8017 Å / Relative weight: 1
ReflectionResolution: 2.8→50 Å / Num. obs: 36767 / % possible obs: 99.4 % / Observed criterion σ(I): 0 / Redundancy: 9.38 % / Rmerge(I) obs: 0.216 / Net I/σ(I): 8.22 / Num. measured all: 345021
Reflection shellResolution: 2.8→2.9 Å / Redundancy: 9.26 % / Rmerge(I) obs: 1.306 / Mean I/σ(I) obs: 1.25 / % possible all: 99.9

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Processing

Software
NameClassification
CNSrefinement
XDSdata reduction
XSCALEdata scaling
CNSphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1NOD

1nod


Resolution: 2.8→19.72 Å / Occupancy max: 1 / Occupancy min: 1 / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.3234 1824 4.9 %RANDOM
Rwork0.2794 34941 --
all-36967 --
obs-36765 99.5 %-
Solvent computationBsol: 39.1985 Å2
Displacement parametersBiso max: 168.12 Å2 / Biso mean: 77.6278 Å2 / Biso min: 1 Å2
Baniso -1Baniso -2Baniso -3
1-23.199 Å2-1.88 Å20 Å2
2--23.199 Å20 Å2
3----46.397 Å2
Refinement stepCycle: LAST / Resolution: 2.8→19.72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6744 0 163 84 6991
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it6.1016
X-RAY DIFFRACTIONc_scbond_it9.028
X-RAY DIFFRACTIONc_mcangle_it9.0288
X-RAY DIFFRACTIONc_scangle_it12.22910

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