Crane B R, Arvai A S, Gachhui R, Wu C, Ghosh D K, Getzoff E D, Stuehr D J, Tainer J A
Department of Molecular Biology and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Science. 1997 Oct 17;278(5337):425-31. doi: 10.1126/science.278.5337.425.
The nitric oxide synthase oxygenase domain (NOSox) oxidizes arginine to synthesize the cellular signal and defensive cytotoxin nitric oxide (NO). Crystal structures determined for cytokine-inducible NOSox reveal an unusual fold and heme environment for stabilization of activated oxygen intermediates key for catalysis. A winged beta sheet engenders a curved alpha-beta domain resembling a baseball catcher's mitt with heme clasped in the palm. The location of exposed hydrophobic residues and the results of mutational analysis place the dimer interface adjacent to the heme-binding pocket. Juxtaposed hydrophobic O2- and polar L-arginine-binding sites occupied by imidazole and aminoguanidine, respectively, provide a template for designing dual-function inhibitors and imply substrate-assisted catalysis.
一氧化氮合酶加氧酶结构域（NOSox）将精氨酸氧化以合成细胞信号和防御性细胞毒素一氧化氮（NO）。对细胞因子诱导型NOSox测定的晶体结构揭示了一种不同寻常的折叠和血红素环境，用于稳定对催化至关重要的活性氧中间体。一个带翼的β折叠形成一个弯曲的α-β结构域，类似于棒球捕手的手套，血红素夹在手掌中。暴露的疏水残基的位置和突变分析的结果表明二聚体界面与血红素结合口袋相邻。分别被咪唑和氨基胍占据的并列疏水O2-和极性L-精氨酸结合位点为设计双功能抑制剂提供了模板，并暗示底物辅助催化。
