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The mobility of a conserved tyrosine residue controls isoform-dependent enzyme-inhibitor interactions in nitric oxide synthases.

Li H, Jamal J, Delker S, Plaza C, Ji H, Jing Q, Huang H, Kang S, Silverman RB, Poulos TL
Biochemistry 53 5272-9 (2014)
Related entries: 4cwv, 4cww, 4cwx, 4cwy, 4cwz, 4cx0, 4cx1, 4cx3, 4cx4, 4cx5, 4cx6, 4cx7

Cited: 12 times
EuropePMC logo PMID: 25089924

Abstract

Many pyrrolidine-based inhibitors highly selective for neuronal nitric oxide synthase (nNOS) over endothelial NOS (eNOS) exhibit dramatically different binding modes. In some cases, the inhibitor binds in a 180° flipped orientation in nNOS relative to eNOS. From the several crystal structures we have determined, we know that isoform selectivity correlates with the rotamer position of a conserved tyrosine residue that H-bonds with a heme propionate. In nNOS, this Tyr more readily adopts the out-rotamer conformation, while in eNOS, the Tyr tends to remain fixed in the original in-rotamer conformation. In the out-rotamer conformation, inhibitors are able to form better H-bonds with the protein and heme, thus increasing inhibitor potency. A segment of polypeptide that runs along the surface near the conserved Tyr has long been thought to be the reason for the difference in Tyr mobility. Although this segment is usually disordered in both eNOS and nNOS, sequence comparisons and modeling from a few structures show that this segment is structured quite differently in eNOS and nNOS. In this study, we have probed the importance of this surface segment near the Tyr by making a few mutants in the region followed by crystal structure determinations. In addition, because the segment near the conserved Tyr is highly ordered in iNOS, we also determined the structure of an iNOS-inhibitor complex. This new structure provides further insight into the critical role that mobility plays in isoform selectivity.

Reviews citing this publication (1)

  1. Nitric oxide synthase and its function in animal reproduction: an update. Zhang W, Chen SJ, Guo LY, Zhang Z, Zhang JB, Wang XM, Meng XB, Zhang MY, Zhang KK, Chen LL, Li YW, Wen Y, Wang L, Hu JH, Bai YY, Zhang XJ. Front Physiol 14 1288669 (2023)

Articles citing this publication (11)

  1. Structures of human constitutive nitric oxide synthases. Li H, Jamal J, Plaza C, Pineda SH, Chreifi G, Jing Q, Cinelli MA, Silverman RB, Poulos TL. Acta Crystallogr D Biol Crystallogr 70 2667-2674 (2014)
  2. Novel 2,4-disubstituted pyrimidines as potent, selective, and cell-permeable inhibitors of neuronal nitric oxide synthase. Mukherjee P, Li H, Sevrioukova I, Chreifi G, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 58 1067-1088 (2015)
  3. 2-Aminopyridines with a Truncated Side Chain To Improve Human Neuronal Nitric Oxide Synthase Inhibitory Potency and Selectivity. Kang S, Li H, Tang W, Martásek P, Roman LJ, Poulos TL, Silverman RB. J. Med. Chem. 58 5548-5560 (2015)
  4. Nitric Oxide Synthase as a Target for Methicillin-Resistant Staphylococcus aureus. Holden JK, Kang S, Beasley FC, Cinelli MA, Li H, Roy SG, Dejam D, Edinger AL, Nizet V, Silverman RB, Poulos TL. Chem. Biol. 22 785-792 (2015)
  5. Phenyl Ether- and Aniline-Containing 2-Aminoquinolines as Potent and Selective Inhibitors of Neuronal Nitric Oxide Synthase. Cinelli MA, Li H, Pensa AV, Kang S, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 58 8694-8712 (2015)
  6. Nitrile in the Hole: Discovery of a Small Auxiliary Pocket in Neuronal Nitric Oxide Synthase Leading to the Development of Potent and Selective 2-Aminoquinoline Inhibitors. Cinelli MA, Li H, Chreifi G, Poulos TL, Silverman RB. J. Med. Chem. 60 3958-3978 (2017)
  7. Fluorination Effects on NOS Inhibitory Activity of Pyrazoles Related to Curcumin. Nieto CI, Cabildo MP, Cornago MP, Sanz D, Claramunt RM, Torralba MC, Torres MR, Elguero J, García JA, López A, Acuña-Castroviejo D. Molecules 20 15643-15665 (2015)
  8. Potent and Selective Human Neuronal Nitric Oxide Synthase Inhibition by Optimization of the 2-Aminopyridine-Based Scaffold with a Pyridine Linker. Wang HY, Qin Y, Li H, Roman LJ, Martásek P, Poulos TL, Silverman RB. J. Med. Chem. 59 4913-4925 (2016)
  9. Inhibitor Bound Crystal Structures of Bacterial Nitric Oxide Synthase. Holden JK, Dejam D, Lewis MC, Huang H, Kang S, Jing Q, Xue F, Silverman RB, Poulos TL. Biochemistry 54 4075-4082 (2015)
  10. Insights into human eNOS, nNOS and iNOS structures and medicinal indications from statistical analyses of their interactions with bound compounds. Dong J, Li D, Kang L, Luo C, Wang J. Biophys Rep 9 159-175 (2023)
  11. Isolation, Identification, Anti-Inflammatory, and In Silico Analysis of New Lignans from the Resin of Ferula sinkiangensis. Wang J, Zheng Q, Shi M, Wang H, Fan C, Wang G, Zhao Y, Si J. Pharmaceuticals (Basel) 16 1351 (2023)


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