Tyrosine 135 of the ß1 subunit as binding site of BAY-543: Importance of the Y-x-S-x-R motif for binding and activation by sGC activator drugs.
Eur J Pharmacol
; 881: 173203, 2020 Aug 15.
Article
em En
| MEDLINE
| ID: mdl-32446711
ABSTRACT
Soluble guanylyl cyclase (sGC), the major receptor for nitric oxide (NO), is a heterodimer consisting of two subunits, the α and the ß subunit. The NO/sGC/cGMP signaling pathway is protective in different disease pathomechanisms including angina pectoris, pulmonary hypertension and fibrotic diseases. The natural ligand heme has two carboxylic acids which interact in the ß1 heme nitric oxide oxygen binding (HNOX) domain with the amino acids of the highly conserved Y-x-S-x-R motif. The Y-x-S-x-R motif is also involved in binding of the dicarboxylic activators cinaciguat and BAY 60-2770 as indicated by crystallization studies of sGC activator and bacterial HNOX homologs. To what extent the Y-x-S-x-R motif hydrogen bond network contributes to binding of monocarboxylic acids has not been examined so far. In the current paper, the chemical structural formula of the novel monocarboxylic drug BAY-543 is described for the first time. Using this novel drug, we evaluate the importance of the amino acids Y135 and R139 for thermostabilization and activation in comparison to the dicarboxylic acid BAY 60-2770. Measurements with point mutated sGC variants demonstrate tyrosine 135 as exclusive binding site of the monocarboxylic acid BAY-543 but not the dicarboxylic BAY 60-2770.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ativadores de Enzimas
/
Guanilil Ciclase Solúvel
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Eur J Pharmacol
Ano de publicação:
2020
Tipo de documento:
Article