2HX3

Rat nNOS heme domain complexed with (4S)-N-{4-Amino-5-[(2-aminoethyl)-hydroxyamino]-pentyl}-N'-nitroguanidine

2HX3 の概要

• エントリーDOI: 10.2210/pdb2hx3/pdb
• 関連するPDBエントリー: 1P6I 2HX2 2HX4
• 分子名称: Nitric-oxide synthase, ACETATE ION, ZINC ION, ... (7 entities in total)
• 機能のキーワード: nitric oxide synthase, heme enzyme, inhibitor, oxidoreductase
• 由来する生物種: Rattus norvegicus (Norway rat)
• 細胞内の位置: Cell membrane, sarcolemma; Peripheral membrane protein (By similarity): P29476
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 100050.61

構造登録者

Igarashi, J.,Li, H.,Poulos, T.L. (登録日: 2006-08-02, 公開日: 2007-04-24, 最終更新日: 2024-02-14)

主引用文献

Seo, J.,Igarashi, J.,Li, H.,Martasek, P.,Roman, L.J.,Poulos, T.L.,Silverman, R.B.
Structure-Based Design and Synthesis of N(omega)-Nitro-l-Arginine-Containing Peptidomimetics as Selective Inhibitors of Neuronal Nitric Oxide Synthase. Displacement of the Heme Structural Water.
J.Med.Chem., 50:2089-2099, 2007

PubMed Abstract: The neuronal isoform of nitric oxide synthase (nNOS), the enzyme responsible for the production of nitric oxide in the central nervous system, represents an attractive target for the treatment of various neurodegenerative disorders. X-ray crystal structures of complexes of nNOS with two nNOS-selective inhibitors, (4S)-N-{4-amino-5-[(2-aminoethylamino]pentyl}-N'-nitroguanidine (1) and 4-N-(Nomega-nitro-l-argininyl)-trans-4-amino-l-proline amide (2), led to the discovery of a conserved structural water molecule that was hydrogen bonded between the two heme propionates and the inhibitors (Figure 2). On the basis of this observation, we hypothesized that by attaching a hydrogen bond donor group to the amide nitrogen of 2 or to the secondary amine nitrogen of 1, the inhibitor molecules could displace the structural water molecule and obtain a direct interaction with the heme cofactor. To test this hypothesis, peptidomimetic analogues 3-5, which have either an N-hydroxyl (3 and 5) or N-amino (4) donor group, were designed and synthesized. X-ray crystal structures of nNOS with inhibitors 3 and 5 bound verified that the N-hydroxyl group had, indeed, displaced the structural water molecule and provided a direct interaction with the heme propionate moiety (Figures 5 and 6). Surprisingly, in vitro activity assay results indicated that the addition of a hydroxyl group (3) only increased the potency slightly against the neuronal isoform over the parent compound (1). Rationalizations for the small increase in potency are consistent with other changes in the crystal structures.

PubMed: 17425297
DOI: 10.1021/jm061305c

実験手法

X-RAY DIFFRACTION (2 Å)