Document Detail


Structure of cinaciguat (BAY 58-2667) bound to Nostoc H-NOX domain reveals insights into heme-mimetic activation of the soluble guanylyl cyclase.
MedLine Citation:
PMID:  20463019     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Heme is a vital molecule for all life forms with heme being capable of assisting in catalysis, binding ligands, and undergoing redox changes. Heme-related dysfunction can lead to cardiovascular diseases with the oxidation of the heme of soluble guanylyl cyclase (sGC) critically implicated in some of these cardiovascular diseases. sGC, the main nitric oxide (NO) receptor, stimulates second messenger cGMP production, whereas reactive oxygen species are known to scavenge NO and oxidize/inactivate the heme leading to sGC degradation. This vulnerability of NO-heme signaling to oxidative stress led to the discovery of an NO-independent activator of sGC, cinaciguat (BAY 58-2667), which is a candidate drug in clinical trials to treat acute decompensated heart failure. Here, we present crystallographic and mutagenesis data that reveal the mode of action of BAY 58-2667. The 2.3-A resolution structure of BAY 58-2667 bound to a heme NO and oxygen binding domain (H-NOX) from Nostoc homologous to that of sGC reveals that the trifurcated BAY 58-2667 molecule has displaced the heme and acts as a heme mimetic. Carboxylate groups of BAY 58-2667 make interactions similar to the heme-propionate groups, whereas its hydrophobic phenyl ring linker folds up within the heme cavity in a planar-like fashion. BAY 58-2667 binding causes a rotation of the alphaF helix away from the heme pocket, as this helix is normally held in place via the inhibitory His(105)-heme covalent bond. The structure provides insights into how BAY 58-2667 binds and activates sGC to rescue heme-NO dysfunction in cardiovascular diseases.
Authors:
Faye Martin; Padmamalini Baskaran; Xiaolei Ma; Pete W Dunten; Martina Schaefer; Johannes-Peter Stasch; Annie Beuve; Focco van den Akker
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2010-05-12
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  285     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2010 Jul 
Date Detail:
Created Date:  2010-07-12     Completed Date:  2010-08-06     Revised Date:  2014-09-18    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  22651-7     Citation Subset:  IM    
Data Bank Information
Bank Name/Acc. No.:
PDB/3L6J
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MeSH Terms
Descriptor/Qualifier:
Benzoates / chemistry*
Crystallography, X-Ray
Enzyme Activation
Enzyme Activators / chemistry
Guanylate Cyclase / chemistry*,  metabolism*
Heme / chemistry*
Models, Molecular
Molecular Mimicry*
Mutagenesis
Nitric Oxide / chemistry*
Nostoc / enzymology*
Protein Structure, Secondary
Protein Structure, Tertiary
Receptors, Cytoplasmic and Nuclear / chemistry*,  metabolism*
Structure-Activity Relationship
Grant Support
ID/Acronym/Agency:
5 P41 RR001209/RR/NCRR NIH HHS; R01 GM067640/GM/NIGMS NIH HHS; R01 HL075329/HL/NHLBI NIH HHS; R01 HL075329/HL/NHLBI NIH HHS; R01 HL075329-04/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
0/Benzoates; 0/Enzyme Activators; 0/Receptors, Cytoplasmic and Nuclear; 31C4KY9ESH/Nitric Oxide; 329773-35-5/BAY 58-2667; 42VZT0U6YR/Heme; EC 4.6.1.2/Guanylate Cyclase; EC 4.6.1.2/soluble guanylyl cyclase
Comments/Corrections

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