Interactions between 2 '-fluoro-(carbamoyl-pyridinyl)deschloroepibatidine analogues and acetylcholine-binding protein inform on potent antagonist activity against nicotinic receptors

Autor(es)

Bueno, Renata, V ; Davis, Samuel ; Dawson, Alice ; Ondachi, Pauline W. ; Carroll, F. Ivy ; Hunter, William N.

• Tipo de documento: Artigo Científico
• Fonte: ACTA CRYSTALLOGRAPHICA SECTION D-STRUCTURAL BIOLOGY; v. 78, p. 10-pg., 2022-03-01.

Resumo

Low-nanomolar binding constants were recorded for a series of six 2'-fluoro-(carbamoylpyridinyl)deschloroepibatidine analogues with acetylcholine-binding protein (AChBP). The crystal structures of three complexes with AChBP reveal details of molecular recognition in the orthosteric binding site and imply how the other three ligands bind. Comparisons exploiting AChBP as a surrogate for alpha 4 beta 2 and alpha 7 nicotinic acetylcholine receptors (nAChRs) suggest that the key interactions are conserved. The ligands interact with the same residues as the archetypal nAChR agonist nicotine yet display greater affinity, thereby rationalizing their in vivo activity as potent antagonists of nicotine-induced antinociception. An oxyanion-binding site is formed on the periphery of the AChBP orthosteric site by Lys42, Asp94, Glu170 and Glu210. These residues are highly conserved in the human alpha 4, beta 2 and alpha 7 nAChR sequences. However, specific sequence differences are discussed that could contribute to nAChR subtype selectivity and in addition may represent a point of allosteric modulation. The ability to engage with this peripheral site may explain, in part, the function of a subset of ligands to act as agonists of alpha 7 nAChR. (AU)

• Processo FAPESP: 16/16038-5 - Exploração de estratégias de triagem para identificar inibidores de n°,5 N10: metilenotetrahidrofolato desidrogenase-ciclohidrolase de Xanthomonas albilineans
• Beneficiário: Renata Vieira Bueno
• Modalidade de apoio: Bolsas no Exterior - Estágio de Pesquisa - Doutorado