3L6J

Structure of cinaciguat (bay 58-2667) bound to nostoc H-NOX domain

Summary for 3L6J

• Entry DOI: 10.2210/pdb3l6j/pdb
• Related: 2O09 2O0C 2O0G
• Descriptor: Alr2278 protein, 4-({(4-carboxybutyl)[2-(2-{[4-(2-phenylethyl)benzyl]oxy}phenyl)ethyl]amino}methyl)benzoic acid (3 entities in total)
• Functional Keywords: guanylyl cyclase, bay58-2667, signaling protein
• Biological source: Nostoc sp.
• Total number of polymer chains: 2
• Total formula weight: 43558.68

Authors

Martin, F.,van den Akker, F. (deposition date: 2009-12-23, release date: 2010-05-12, Last modification date: 2023-09-06)

Primary citation

Martin, F.,Baskaran, P.,Ma, X.,Dunten, P.W.,Schaefer, M.,Stasch, J.P.,Beuve, A.,van den Akker, F.
Structure of cinaciguat (BAY 58-2667) bound to Nostoc H-NOX domain reveals insights into heme-mimetic activation of the soluble guanylyl cyclase.
J.Biol.Chem., 285:22651-22657, 2010

PubMed Abstract: 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.

PubMed: 20463019
DOI: 10.1074/jbc.M110.111559

Experimental method

X-RAY DIFFRACTION (2.3 Å)