Binding of YC-1 or BAY 41-2272 to soluble guanylyl cyclase induces a geminate phase in CO photolysis

Xiaohui Hu, Changjian Feng, James T. Hazzard, Gordon Tollin, William "Bill" Montfort

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Soluble guanylyl/guanylate cyclase (sGC), a heme-containing heterodimeric protein of ∼150 kDa, is the primary receptor for nitric oxide, an endogenous molecule of immense physiological importance to animals. Recent studies have identified compounds such as YC-1 and BAY 41-2272 that stimulate sGC independently of NO binding, properties of importance for the treatment of endothelial dysfunction and other diseases linked to malfunctioning NO signaling pathways. We have developed a novel expression system for sGC from Manduca sexta (the tobacco hornworm) that retains the N-terminal two-thirds of both subunits, including heme, but is missing the catalytic domain. Here, we show that binding of compounds YC-1 or BAY 41-2272 to the truncated protein leads to a change in the heme pocket such that photolyzed CO cannot readily escape from the protein matrix. Geminate recombination of the trapped CO molecules with heme takes place with a measured rate of 6 × 107 s-1. These findings provide strong support for an allosteric regulatory model in which YC-1 and related compounds can alter the sGC heme pocket conformation to retain diatomic ligands and thus activate the enzyme alone or in synergy with either NO or CO.

Original languageEnglish (US)
Pages (from-to)15748-15749
Number of pages2
JournalJournal of the American Chemical Society
Volume130
Issue number47
DOIs
StatePublished - Nov 26 2008

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Photolysis
Guanylate Cyclase
Carbon Monoxide
Heme
Proteins
Molecules
Tobacco
Nitric oxide
Manduca
Conformations
Animals
Enzymes
Ligands
Nitric Oxide
3-(4-Amino-5-cyclopropylpyrimidine-2-yl)-1-(2-fluorobenzyl)-1H-pyrazolo(3,4-b)pyridine
Soluble Guanylyl Cyclase
Genetic Recombination
Catalytic Domain

ASJC Scopus subject areas

  • Chemistry(all)
  • Catalysis
  • Biochemistry
  • Colloid and Surface Chemistry

Cite this

Binding of YC-1 or BAY 41-2272 to soluble guanylyl cyclase induces a geminate phase in CO photolysis. / Hu, Xiaohui; Feng, Changjian; Hazzard, James T.; Tollin, Gordon; Montfort, William "Bill".

In: Journal of the American Chemical Society, Vol. 130, No. 47, 26.11.2008, p. 15748-15749.

Research output: Contribution to journalArticle

Hu, Xiaohui ; Feng, Changjian ; Hazzard, James T. ; Tollin, Gordon ; Montfort, William "Bill". / Binding of YC-1 or BAY 41-2272 to soluble guanylyl cyclase induces a geminate phase in CO photolysis. In: Journal of the American Chemical Society. 2008 ; Vol. 130, No. 47. pp. 15748-15749.
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