Structural highlights
1dwx is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
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| Ligands: | , , , |
| Related: | 1dwv, 1dww, 1qom, 1noc, 1nos, 2nos, 1nod, 2nod, 3nod |
| Activity: | Nitric-oxide synthase (NADPH dependent), with EC number 1.14.13.39 |
| Resources: | FirstGlance, OCA, RCSB, PDBsum |
Function
[NOS2_MOUSE] Produces nitric oxide (NO) which is a messenger molecule with diverse functions throughout the body. In macrophages, NO mediates tumoricidal and bactericidal actions. Also has nitrosylase activity and mediates cysteine S-nitrosylation of cytoplasmic target proteins such COX2.[1]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Nitric oxide synthases (NOSs) catalyze two mechanistically distinct, tetrahydrobiopterin (H(4)B)-dependent, heme-based oxidations that first convert L-arginine (L-Arg) to N(omega)-hydroxy-L-arginine (NHA) and then NHA to L-citrulline and nitric oxide. Structures of the murine inducible NOS oxygenase domain (iNOS(ox)) complexed with NHA indicate that NHA and L-Arg both bind with the same conformation adjacent to the heme iron and neither interacts directly with it nor with H(4)B. Steric restriction of dioxygen binding to the heme in the NHA complex suggests either small conformational adjustments in the ternary complex or a concerted reaction of dioxygen with NHA and the heme iron. Interactions of the NHA hydroxyl with active center beta-structure and the heme ring polarize and distort the hydroxyguanidinium to increase substrate reactivity. Steric constraints in the active center rule against superoxo-iron accepting a hydrogen atom from the NHA hydroxyl in their initial reaction, but support an Fe(III)-peroxo-NHA radical conjugate as an intermediate. However, our structures do not exclude an oxo-iron intermediate participating in either L-Arg or NHA oxidation. Identical binding modes for active H(4)B, the inactive quinonoid-dihydrobiopterin (q-H(2)B), and inactive 4-amino-H(4)B indicate that conformational differences cannot explain pterin inactivity. Different redox and/or protonation states of q-H(2)B and 4-amino-H(4)B relative to H(4)B likely affect their ability to electronically influence the heme and/or undergo redox reactions during NOS catalysis. On the basis of these structures, we propose a testable mechanism where neutral H(4)B transfers both an electron and a 3,4-amide proton to the heme during the first step of NO synthesis.
Structures of the N(omega)-hydroxy-L-arginine complex of inducible nitric oxide synthase oxygenase dimer with active and inactive pterins.,Crane BR, Arvai AS, Ghosh S, Getzoff ED, Stuehr DJ, Tainer JA Biochemistry. 2000 Apr 25;39(16):4608-21. PMID:10769116[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kim SF, Huri DA, Snyder SH. Inducible nitric oxide synthase binds, S-nitrosylates, and activates cyclooxygenase-2. Science. 2005 Dec 23;310(5756):1966-70. PMID:16373578 doi:http://dx.doi.org/10.1126/science.1119407
- ↑ Crane BR, Arvai AS, Ghosh S, Getzoff ED, Stuehr DJ, Tainer JA. Structures of the N(omega)-hydroxy-L-arginine complex of inducible nitric oxide synthase oxygenase dimer with active and inactive pterins. Biochemistry. 2000 Apr 25;39(16):4608-21. PMID:10769116
