Ajulemic acid, a synthetic nonpsychoactive cannabinoid acid, bound to the ligand binding domain of the human peroxisome proliferator-activated receptor gamma

Autor(es)

Ambrosio, Andre L. B. ; Dias, Sandra M. G. ; Polikarpov, Igor ^[3] ; Zurier, Robert B. ; Burstein, Sumner H. ; Garratt, Richard C.

• Tipo de documento: Artigo Científico
• Fonte: Journal of Biological Chemistry; v. 282, n. 25, p. 18625-18633, June 2007.
• Área do conhecimento: Ciências Biológicas - Biofísica
• Assunto(s): Biofísica Canabinoides Receptores ativados por proliferador de peroxissomo

Resumo

Ajulemic acid (AJA) is a synthetic analog of THC-11-oic acid, a metabolite of tetrahydrocannabinol (THC), the major active ingredient of the recreational drug marijuana derived from the plant Cannabis sativa. AJA has potent analgesic and anti-inflammatory activity in vivo, but without the psychotropic action of THC. However, its precise mechanism of action remains unknown. Biochemical studies indicate that AJA binds directly and selectively to the isotype gamma of the peroxisome proliferator-activated receptor (PPAR gamma) suggesting that this may be a pharmacologically relevant receptor for this compound and a potential target for drug development in the treatment of pain and inflammation. Here, we report the crystal structure of the ligand binding domain of the gamma isotype of human PPAR in complex with ajulemic acid, determined at 2.8-angstrom resolution. Our results show a binding mode that is compatible with other known partial agonists of PPAR, explaining their moderate activation of the receptor, as well as the structural basis for isotype selectivity, as observed previously in vitro. The structure also provides clues to the understanding of partial agonism itself, suggesting a rational approach to the design of molecules capable of activating the receptor at levels that avoid undesirable side effects. (AU)

• Processo FAPESP: 06/00182-8 - Biofísica estrutural dos receptores nucleares e proteínas relacionadas
• Beneficiário: Igor Polikarpov
• Linha de fomento: Auxílio à Pesquisa - Temático
• Processo FAPESP: 98/14138-2 - Center for Structural Molecular Biotechnology
• Beneficiário: Glaucius Oliva
• Linha de fomento: Auxílio à Pesquisa - Centros de Pesquisa, Inovação e Difusão - CEPIDs
• Processo FAPESP: 03/00231-0 - Estudos estruturais de receptores-gama ativados por proliferadores de peroxissomo (PPAR-y)
• Beneficiário: Andre Luis Berteli Ambrosio
• Linha de fomento: Bolsas no Brasil - Doutorado
• Processo FAPESP: 99/03387-4 - Estudos estruturais de proteínas usando luz síncrotron
• Beneficiário: Igor Polikarpov
• Linha de fomento: Auxílio à Pesquisa - Temático