1TLL

CRYSTAL STRUCTURE OF RAT NEURONAL NITRIC-OXIDE SYNTHASE REDUCTASE MODULE AT 2.3 A RESOLUTION.

Summary for 1TLL

• Entry DOI: 10.2210/pdb1tll/pdb
• Related: 1F20
• Descriptor: Nitric-oxide synthase, brain, SULFITE ION, FLAVIN MONONUCLEOTIDE, ... (6 entities in total)
• Functional Keywords: nitric-oxide synthase, reductase module, fmn, fad, nadp+, oxidoreductase
• Biological source: Rattus norvegicus (Norway rat)
• Cellular location: Cell membrane, sarcolemma; Peripheral membrane protein (By similarity): P29476
• Total number of polymer chains: 2
• Total formula weight: 160149.24

Authors

Garcin, E.D.,Bruns, C.M.,Lloyd, S.J.,Hosfield, D.J.,Tiso, M.,Gachhui, R.,Stuehr, D.J.,Tainer, J.A.,Getzoff, E.D. (deposition date: 2004-06-09, release date: 2004-08-31, Last modification date: 2023-08-23)

Primary citation

Garcin, E.D.,Bruns, C.M.,Lloyd, S.J.,Hosfield, D.J.,Tiso, M.,Gachhui, R.,Stuehr, D.J.,Tainer, J.A.,Getzoff, E.D.
Structural basis for isozyme-specific regulation of electron transfer in nitric-oxide synthase
J.Biol.Chem., 279:37918-37927, 2004

PubMed Abstract: Three nitric-oxide synthase (NOS) isozymes play crucial, but distinct, roles in neurotransmission, vascular homeostasis, and host defense, by catalyzing Ca(2+)/calmodulin-triggered NO synthesis. Here, we address current questions regarding NOS activity and regulation by combining mutagenesis and biochemistry with crystal structure determination of a fully assembled, electron-supplying, neuronal NOS reductase dimer. By integrating these results, we structurally elucidate the unique mechanisms for isozyme-specific regulation of electron transfer in NOS. Our discovery of the autoinhibitory helix, its placement between domains, and striking similarities with canonical calmodulin-binding motifs, support new mechanisms for NOS inhibition. NADPH, isozyme-specific residue Arg(1400), and the C-terminal tail synergistically repress NOS activity by locking the FMN binding domain in an electron-accepting position. Our analyses suggest that calmodulin binding or C-terminal tail phosphorylation frees a large scale swinging motion of the entire FMN domain to deliver electrons to the catalytic module in the holoenzyme.

PubMed: 15208315
DOI: 10.1074/jbc.M406204200

Experimental method

X-RAY DIFFRACTION (2.3 Å)