Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase
- Title
- Structural basis for dipeptide amide isoform-selective inhibition of neuronal nitric oxide synthase
- Author
- 하정미
- Issue Date
- 2004-01
- Publisher
- NATURE PUBLISHING GROUP
- Citation
- NATURE STRUCTURAL & MOLECULAR BIOLOGY, v. 11, No. 1, Page. 54-59
- Abstract
- Three nitric oxide synthase (NOS) isoforms, eNOS, nNOS and iNOS, generate nitric oxide (NO) crucial to the cardiovascular, nervous and host defense systems, respectively. Development of isoform-selective NOS inhibitors is of considerable therapeutic importance. Crystal structures of nNOS-selective dipeptide inhibitors in complex with both nNOS and eNOS were solved and the inhibitors were found to adopt a curled conformation in nNOS but an extended conformation in eNOS. We hypothesized that a single-residue difference in the active site, Asp597 (nNOS) versus Asn368 (eNOS), is responsible for the favored binding in nNOS. In the D597N nNOS mutant crystal structure, a bound inhibitor switches to the extended conformation and its inhibition of nNOS decreases >200-fold. Therefore, a single-residue difference is responsible for more than two orders of magnitude selectivity in inhibition of nNOS over eNOS by L-Nω-nitroarginine-containing dipeptide inhibitors.
- URI
- https://www.nature.com/articles/nsmb704https://repository.hanyang.ac.kr/handle/20.500.11754/132007
- ISSN
- 1545-9993; 1545-9985
- DOI
- 10.1038/nsmb704
- Appears in Collections:
- COLLEGE OF PHARMACY[E](약학대학) > PHARMACY(약학과) > Articles
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