Implications for Isoform-selective Inhibitor Design Derived from the Binding Mode of Bulky Isothioureas to the Heme Domain of Endothelial Nitric-oxide Synthase

C. S. Raman, Huiying Li, Pavel Martásek, Boga Ramesh Babu, Owen W. Griffith, Bettie Sue S Masters, Thomas L. Poulos

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Nitric oxide produced by nitric-oxide synthase (NOS) is not only involved in a wide range of physiological functions but also in a variety of pathological conditions. Isoform-selective NOS inhibitors are highly desirable to regulate the NO production of one isoform beneficial to normal physiological functions from the uncontrolled NO production of another isoform that accompanies certain pathological states. Crystal structures of the heme domain of the three NOS isoforms have revealed a very high degree of similarity in the immediate vicinity of the heme active site illustrating the challenge of isoform-selective inhibitor design. Isothioureas are potent NOS inhibitors, and the structures of the endothelial NOS heme domain complexed with isothioureas bearing small S-alkyl substituents have been determined (Li, H., Raman, C.S., Martásek, P., Král, V., Masters, B.S.S., and Poulos, T.L. (2000) J. Inorg. Bio. chem. 81, 133-139). In the present communication, the binding mode of larger bisisothioureas complexed to the endothelial NOS heme domain has been determined. These structures afford a structural rationale for the known inhibitory activities. In addition, these structures provide clues on how to exploit the longer inhibitor substituents that extend out of the active site pocket for isoform-selective inhibitor design.

Original languageEnglish (US)
Pages (from-to)26486-26491
Number of pages6
JournalJournal of Biological Chemistry
Volume276
Issue number28
DOIs
StatePublished - Jul 13 2001

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Nitric Oxide Synthase Type III
Heme
Protein Isoforms
Nitric Oxide Synthase
Catalytic Domain
Bearings (structural)
Nitric Oxide
Crystal structure
Communication

ASJC Scopus subject areas

  • Biochemistry

Cite this

Implications for Isoform-selective Inhibitor Design Derived from the Binding Mode of Bulky Isothioureas to the Heme Domain of Endothelial Nitric-oxide Synthase. / Raman, C. S.; Li, Huiying; Martásek, Pavel; Babu, Boga Ramesh; Griffith, Owen W.; Masters, Bettie Sue S; Poulos, Thomas L.

In: Journal of Biological Chemistry, Vol. 276, No. 28, 13.07.2001, p. 26486-26491.

Research output: Contribution to journalArticle

Raman, C. S. ; Li, Huiying ; Martásek, Pavel ; Babu, Boga Ramesh ; Griffith, Owen W. ; Masters, Bettie Sue S ; Poulos, Thomas L. / Implications for Isoform-selective Inhibitor Design Derived from the Binding Mode of Bulky Isothioureas to the Heme Domain of Endothelial Nitric-oxide Synthase. In: Journal of Biological Chemistry. 2001 ; Vol. 276, No. 28. pp. 26486-26491.
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