Molecular Determinants for the Binding Mode of Alkylphosphocholines in the C2 Domain of PKC alpha

Autor(es)

de Sa, Matheus M. ^{[1, 2]} ; Rangel-Yagui, Carlota O. ^[3]

Afiliação do(s) autor(es)

^[1] Univ Sao Paulo, Dept Pharm, BR-05508900 Sao Paulo, SP - Brazil

^[2] Univ Sao Paulo, Lab Genet & Cardiol Mol, Inst Coracao InCor, Fac Med, BR-05403000 Sao Paulo, SP - Brazil

^[3] Univ Sao Paulo, Dept Pharmaceut & Biochem Technol, BR-05508900 Sao Paulo, SP - Brazil

• Tipo de documento: Artigo Científico
• Fonte: MOLECULAR INFORMATICS; v. 34, n. 2-3, p. 84-96, FEB 2015.
• Citações Web of Science: 1

Resumo

Alkylphosphocholines (APCs) and alkyl-lysophos-phocholines (ALPs) are antineoplastic agents that interfere with cellular membranes and signaling proteins. Protein kinase C alpha (PKC alpha) is a signaling protein composed by catalytic (C3, C4) and regulatory domains (C1, C2). The C2 needs calcium (Ca2+) and phosphatidylserine (PS) for activation. Miltefosine inhibits PKC alpha competitively with regard to PS and non-competitively with regard to Ca2+, however, the mechanism of action is unknown. We employed molecular docking, molecular dynamics and chemometric methods to verify how 7 APCs and ALPs derivatives and PS interact with the C2 domain. All ligands except PS were grouped in 2 clusters according to their interactions inside the enzyme. The findings showed that PS's phosphoryl oxygens interact with Ca2+, the serine moiety interacts with Asn189, and the carbonyl oxygen of the alkylic chain interacts with Arg249 and Thr251. On the other hand, ligands' phosphoryl oxygens interact with Asn189, Arg249, Thr250, and one water molecule instead of Ca2+. Because of the different binding mode, we hypothesize that the ligands cause conformational changes in the calcium binding region. Moreover, the packing mismatch between bilayer-forming lipids and ALP/APC chain impedes the C2 domain from docking to the internal leaflet of cellular membranes, interrupting PKC alpha activation. (AU)

• Processo FAPESP: 11/02189-8 - Planejamento e síntese de alquilfosfocolinas como potenciais antineoplásicos
• Beneficiário: Carlota de Oliveira Rangel Yagui
• Modalidade de apoio: Auxílio à Pesquisa - Regular