Diverse dynamics features of novel protein kinase C (PKC) isozymes determine the selectivity of a fluorinated balanol analogue for PKCÎµ.

Hardianto, Ari; Khanna, Varun; Liu, Fei; Ranganathan, Shoba

Hardianto, Ari; Khanna, Varun; Liu, Fei; Ranganathan, Shoba.

Afiliación

Hardianto A; Department of Molecular Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
Khanna V; Department of Chemistry, Universitas Padjadjaran, Jatinangor, West Java, 45363, Indonesia.
Liu F; Department of Molecular Sciences, Macquarie University, Sydney, NSW, 2109, Australia.
Ranganathan S; School of Medicine, Faculty of Medicine, Nursing and Health Sciences, Flinders University, Adelaide, SA, 5042, Australia.

BMC Bioinformatics ; 19(Suppl 13): 342, 2019 Feb 04.

Article en En | MEDLINE | ID: mdl-30717648

RESUMEN

BACKGROUND: (-)-Balanol is an ATP-mimicking inhibitor that non-selectively targets protein kinase C (PKC) isozymes and cAMP-dependent protein kinase (PKA). While PKA constantly shows tumor promoting activities, PKC isozymes can ambiguously be tumor promoters or suppressors. In particular, PKCÎµ is frequently implicated in tumorigenesis and a potential target for anticancer drugs. We recently reported that the C5(S)-fluorinated balanol analogue (balanoid 1c) had improved binding affinity and selectivity for PKCÎµ but not to the other novel PKC isozymes, which share a highly similar ATP site. The underlying basis for this fluorine-based selectivity is not entirely comprehended and needs to be investigated further for the development of ATP mimic inhibitors specific for PKCÎµ. RESULTS: Using molecular dynamics (MD) simulations assisted by homology modelling and sequence analysis, we have studied the fluorine-based selectivity in the highly similar ATP sites of novel PKC (nPKC) isozymes. The study suggests that every nPKC isozyme has different dynamics behaviour in both apo and 1c-bound forms. Interestingly, the apo form of PKCÎµ, where 1c binds strongly, shows the highest degree of flexibility which dramatically decreases after binding 1c. CONCLUSIONS: For the first time to the best of our knowledge, we found that the origin of 1c selectivity for PKCÎµ comes from the unique dynamics feature of each PKC isozyme. Fluorine conformational control in 1c can synergize with and lock down the dynamics of PKCÎµ, which optimize binding interactions with the ATP site residues of the enzyme, particularly the invariant Lys437. This finding has implications for further rational design of balanol-based PKCÎµ inhibitors for cancer drug development.

Asunto(s)

Azepinas/metabolismo; Halogenación; Hidroxibenzoatos/metabolismo; Proteína Quinasa C-epsilon/metabolismo; Adenosina Trifosfato/metabolismo; Azepinas/química; Análisis por Conglomerados; Humanos; Hidroxibenzoatos/química; Isoenzimas/metabolismo; Simulación de Dinámica Molecular; Fosforilación; Conformación Proteica; Proteína Quinasa C-epsilon/química; Ribosa/química; Alineación de Secuencia; Electricidad Estática; Especificidad por Sustrato

Palabras clave

Fluorinated balanol analogue selectivity; Molecular dynamics simulations; Novel PKC isozymes; PKCÎµ; Unique dynamics feature

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Azepinas / Proteína Quinasa C-epsilon / Halogenación / Hidroxibenzoatos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: BMC Bioinformatics Asunto de la revista: INFORMATICA MEDICA Año: 2019 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Reino Unido

Texto completo

Añadir a Mi BVS

Imprimir

XML

PubMed Links

Buscar en Google