与抑制剂AR-R17477复合的一氧化氮合酶同工型的结构为特异性和抑制剂设计提供了合理依据。
Structures of nitric oxide synthase isoforms complexed with the inhibitor AR-R17477 suggest a rational basis for specificity and inhibitor design.
作者信息
Fedorov Roman, Vasan Ryan, Ghosh Dipak K, Schlichting Ilme
机构信息
Max Planck Institut für Molekulare Physiologie, Abteilung Biophysikalische Chemie, Otto Hahn Strasse 11, 44227 Dortmund, Germany.
出版信息
Proc Natl Acad Sci U S A. 2004 Apr 20;101(16):5892-7. doi: 10.1073/pnas.0306588101. Epub 2004 Apr 7.
Abstract
The high level of amino acid conservation and structural similarity of the substrate-binding sites of the oxygenase domains of the nitric oxide synthase (NOS) isoforms (eNOSoxy, iNOSoxy, nNOSoxy) make the interpretation of the structural basis of inhibitor isoform specificity a challenge, and provide few clues for the design of new selective compounds. Crystal structures of iNOSoxy and nNOSoxy complexed with the neuronal NOS-specific inhibitor AR-R17447 suggest that specificity is provided by the interaction of the chlorophenyl group with an isoform-unique substrate access channel residue (L337 in rat neuronal NOS, N115 in mouse inducible NOS). This is confirmed by biochemical analysis of site-directed mutants. Inhibitors combining guanidinium-like structural motifs with long chains specifically targeting this residue are good candidates for rational isoform-specific drug design. Based on this finding, modifications of AR-R17447 to improve the specificity for the human isoforms are suggested.
摘要
一氧化氮合酶（NOS）亚型（内皮型一氧化氮合酶氧合结构域（eNOSoxy）、诱导型一氧化氮合酶氧合结构域（iNOSoxy）、神经型一氧化氮合酶氧合结构域（nNOSoxy））底物结合位点的高氨基酸保守性和结构相似性，使得解释抑制剂亚型特异性的结构基础成为一项挑战，并且为新型选择性化合物的设计提供的线索很少。iNOSoxy和nNOSoxy与神经元型NOS特异性抑制剂AR-R17447复合的晶体结构表明，特异性是由氯苯基与亚型独特的底物进入通道残基（大鼠神经元型NOS中的L337、小鼠诱导型NOS中的N115）之间的相互作用提供的。定点突变体的生化分析证实了这一点。将胍样结构基序与专门靶向该残基的长链相结合的抑制剂，是合理的亚型特异性药物设计的良好候选物。基于这一发现，建议对AR-R17447进行修饰以提高对人类亚型的特异性。
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