Structure of Cinaciguat (BAY 58–2667) Bound to Nostoc H-NOX Domain Reveals Insights into Heme-mimetic Activation of the Soluble Guanylyl Cyclase

• DOI: 10.1074/jbc.m110.111559
• Publication Date: 2010-05-13T00:12:47Z
• Authors: Faye Martin; Padmamalini Baskaran; Xiaolei Ma; Pete W. Dunten; Martina Schaefer; Johannes-Peter St...; Annie Beuve; Focco van den Akker
• Keywords: Soluble guanylyl cyclase

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 the oxidation soluble guanylyl cyclase (sGC) critically implicated some these diseases. sGC, main nitric oxide (NO) receptor, stimulates second messenger cGMP production, whereas reactive oxygen species are known scavenge NO oxidize/inactivate leading sGC degradation. This vulnerability NO-heme signaling oxidative stress led discovery an NO-independent activator cinaciguat (BAY 58-2667), which candidate drug clinical trials treat acute decompensated heart failure. Here, we present crystallographic mutagenesis data that reveal mode action BAY 58-2667. The 2.3-A resolution structure 58-2667 bound domain (H-NOX) from Nostoc homologous reveals trifurcated has displaced acts as mimetic. Carboxylate groups make interactions similar heme-propionate groups, its hydrophobic phenyl ring linker folds up within cavity planar-like fashion. causes rotation alphaF helix away pocket, this normally held place via inhibitory His(105)-heme covalent bond. provides insights into how binds activates rescue heme-NO