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Entry
Database: PDB / ID: 2y37
TitleThe discovery of novel, potent and highly selective inhibitors of inducible nitric oxide synthase (iNOS)
ComponentsNITRIC OXIDE SYNTHASE, INDUCIBLE
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 / 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
Chem-A54 / 5,6,7,8-TETRAHYDROBIOPTERIN / PROTOPORPHYRIN IX CONTAINING FE / Nitric oxide synthase, inducible
Similarity search - Component
Biological speciesMUS MUSCULUS (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.6 Å
AuthorsCheshire, D.R. / Andrews, G. / Beaton, H.G. / Birkinshaw, T.N. / 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.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. / Luker, T. / Mete, A. / Millichip, I. / Nicholls, D.J. / Pimm, A.D. / St-Gallay, S.A. / Wallace, A.V.
CitationJournal: 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. / Berg, A. / Andersson, G.M. / 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. ...Authors: Cheshire, D.R. / Berg, A. / Andersson, G.M. / 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.
History
DepositionDec 19, 2010Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 13, 2011Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 17, 2018Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)103,00313
Polymers100,2422
Non-polymers2,76111
Water5,423301
1
A: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules

A: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)103,09914
Polymers100,2422
Non-polymers2,85712
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation9_555-x,-x+y,-z+2/31
Buried area9460 Å2
ΔGint-131.6 kcal/mol
Surface area33290 Å2
MethodPISA
2
B: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules

B: NITRIC OXIDE SYNTHASE, INDUCIBLE
hetero molecules


Theoretical massNumber of molelcules
Total (without water)102,90712
Polymers100,2422
Non-polymers2,66510
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation11_554-x+y,y,-z-1/21
Buried area9140 Å2
ΔGint-89.7 kcal/mol
Surface area33910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)212.492, 212.492, 115.372
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-1498-

SO4

21A-2143-

HOH

31B-2121-

HOH

41B-2137-

HOH

Noncrystallographic symmetry (NCS)NCS oper: (Code: given
Matrix: (-0.86116, -0.50831, -0.00381), (-0.50832, 0.86111, 0.0096), (-0.0016, 0.0102, -0.99995)
Vector: -0.50714, -0.31278, 10.22265)

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Components

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Protein , 1 types, 2 molecules AB

#1: Protein NITRIC OXIDE SYNTHASE, INDUCIBLE / / INDUCIBLE NITRIC OXID SYNTHASE / INDUCIBLE NOS / MACROPHAGE NOS / NOS TYPE II / MAC-NOS


Mass: 50120.953 Da / Num. of mol.: 2 / Fragment: OXYGENASE DOMAIN, RESIDUES 66-498
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) MUS MUSCULUS (house mouse) / Production host: ESCHERICHIA COLI (E. coli) / Strain (production host): BL23 (DE3) / References: UniProt: P29477, nitric-oxide synthase (NADPH)

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Non-polymers , 6 types, 312 molecules

#2: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-A54 / 2-[(1R)-3-amino-1-phenyl-propoxy]-4-chloro-benzonitrile / AR-C141954


Mass: 286.756 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H15ClN2O
#5: Chemical ChemComp-HEM / PROTOPORPHYRIN IX CONTAINING FE / HEME / Heme B


Mass: 616.487 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C34H32FeN4O4
#6: 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
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 301 / 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: 3.69 Å3/Da / Density % sol: 67 % / Description: 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: 1.059
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Oct 18, 1999
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.059 Å / Relative weight: 1
ReflectionResolution: 2.6→37.8 Å / Num. obs: 47095 / % possible obs: 99.1 % / Observed criterion σ(I): 1 / Redundancy: 4 % / Biso Wilson estimate: 65.68 Å2 / Rmerge(I) obs: 0.07 / Net I/σ(I): 12.9
Reflection shellResolution: 2.6→2.74 Å / Redundancy: 3.1 % / Rmerge(I) obs: 0.57 / Mean I/σ(I) obs: 2 / % possible all: 97.3

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Processing

Software
NameVersionClassification
BUSTER2.9.5refinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.6→26.21 Å / Cor.coef. Fo:Fc: 0.9299 / Cor.coef. Fo:Fc free: 0.9096 / SU R Cruickshank DPI: 0.342 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.352 / SU Rfree Blow DPI: 0.247 / SU Rfree Cruickshank DPI: 0.247
Details: NCS REPRESENTATION : RESTRAINT LSSR ( -AUTONCS). IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=HEM H4B GOL. NUMBER OF ATOMS WITH PROPER CCP4 ATOM ...Details: NCS REPRESENTATION : RESTRAINT LSSR ( -AUTONCS). IDEAL-DIST CONTACT TERM CONTACT SETUP. RESIDUE TYPES WITHOUT CCP4 ATOM TYPE IN LIBRARY=HEM H4B GOL. NUMBER OF ATOMS WITH PROPER CCP4 ATOM TYPE= 7090. NUMBER WITH APPROX DEFAULT CCP4 ATOM TYPE=130. NUMBER TREATED BY BAD NON-BONDED CONTACTS=2.
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 2389 5.08 %RANDOM
Rwork0.208 ---
obs0.2097 46994 99.06 %-
Displacement parametersBiso mean: 56.93 Å2
Baniso -1Baniso -2Baniso -3
1-4.4096 Å20 Å20 Å2
2--4.4096 Å20 Å2
3----8.8191 Å2
Refine analyzeLuzzati coordinate error obs: 0.345 Å
Refinement stepCycle: LAST / Resolution: 2.6→26.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms6718 0 187 301 7206
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.017132HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.159724HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d2404SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes172HARMONIC2
X-RAY DIFFRACTIONt_gen_planes1047HARMONIC5
X-RAY DIFFRACTIONt_it7132HARMONIC20
X-RAY DIFFRACTIONt_nbd2SEMIHARMONIC5
X-RAY DIFFRACTIONt_omega_torsion3.05
X-RAY DIFFRACTIONt_other_torsion19.97
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion876SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact8502SEMIHARMONIC4
LS refinement shellResolution: 2.6→2.67 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.3184 165 4.96 %
Rwork0.2363 3164 -
all0.2404 3329 -
obs--99.06 %

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