View source for 1dd7

[[Image:1dd7.gif|left|200px]]

 {{Structure
|PDB= 1dd7 |SIZE=350|CAPTION= <scene name='initialview01'>1dd7</scene>, resolution 2.25&Aring;
|SITE= 
|LIGAND= <scene name='pdbligand=1PM:N-[(1,3-BENZODIOXOL-5-YL)METHYL]-1-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]-+4-(METHOXYCARBONYL)-PIPERAZINE-2-ACETAMIDE'>1PM</scene>, <scene name='pdbligand=HEM:PROTOPORPHYRIN+IX+CONTAINING+FE'>HEM</scene>, <scene name='pdbligand=SO3:SULFITE+ION'>SO3</scene>
|ACTIVITY= <span class='plainlinks'>[http://en.wikipedia.org/wiki/Nitric-oxide_synthase Nitric-oxide synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.14.13.39 1.14.13.39] </span>
|GENE= 
|DOMAIN=
|RELATEDENTRY=[[1nos|1NOS]], [[1noc|1NOC]], [[1nod|1NOD]], [[2nos|2NOS]], [[1nsi|1NSI]]
|RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1dd7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dd7 OCA], [http://www.ebi.ac.uk/pdbsum/1dd7 PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1dd7 RCSB]</span>
}}

'''MURINE INDUCIBLE NITRIC OXIDE SYNTHASE OXYGENASE DOMAIN (DELTA 114) (N-[(1,3-BENZODIOXOL-5-YL)METHYL]-1-[2-(1H-IMIDAZOL-1-YL)PYRIMIDIN-4-YL]-4-(METHOXYCARBONYL)-PIPERAZINE-2-ACETAMIDE COMPLEX'''


==Overview==
Potent and selective inhibitors of inducible nitric oxide synthase (iNOS) (EC ) were identified in an encoded combinatorial chemical library that blocked human iNOS dimerization, and thereby NO production. In a cell-based iNOS assay (A-172 astrocytoma cells) the inhibitors had low-nanomolar IC(50) values and thus were &gt;1,000-fold more potent than the substrate-based direct iNOS inhibitors 1400W and N-methyl-l-arginine. Biochemical studies confirmed that inhibitors caused accumulation of iNOS monomers in mouse macrophage RAW 264.7 cells. High affinity (K(d) approximately 3 nM) of inhibitors for isolated iNOS monomers was confirmed by using a radioligand binding assay. Inhibitors were &gt;1,000-fold selective for iNOS versus endothelial NOS dimerization in a cell-based assay. The crystal structure of inhibitor bound to the monomeric iNOS oxygenase domain revealed inhibitor-heme coordination and substantial perturbation of the substrate binding site and the dimerization interface, indicating that this small molecule acts by allosterically disrupting protein-protein interactions at the dimer interface. These results provide a mechanism-based approach to highly selective iNOS inhibition. Inhibitors were active in vivo, with ED(50) values of &lt;2 mg/kg in a rat model of endotoxin-induced systemic iNOS induction. Thus, this class of dimerization inhibitors has broad therapeutic potential in iNOS-mediated pathologies.

==About this Structure==
1DD7 is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1DD7 OCA]. 

==Reference==
Allosteric inhibitors of inducible nitric oxide synthase dimerization discovered via combinatorial chemistry., McMillan K, Adler M, Auld DS, Baldwin JJ, Blasko E, Browne LJ, Chelsky D, Davey D, Dolle RE, Eagen KA, Erickson S, Feldman RI, Glaser CB, Mallari C, Morrissey MM, Ohlmeyer MH, Pan G, Parkinson JF, Phillips GB, Polokoff MA, Sigal NH, Vergona R, Whitlow M, Young TA, Devlin JJ, Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1506-11. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/10677491 10677491]
[[Category: Mus musculus]]
[[Category: Nitric-oxide synthase]]
[[Category: Single protein]]
[[Category: Adler, M.]]
[[Category: Whitlow, M.]]
[[Category: dimerization]]
[[Category: heme]]
[[Category: inhibitor]]
[[Category: l-arginine monooxygenase]]
[[Category: nitric oxide]]
[[Category: no]]

''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:39:20 2008''