4 research outputs found
Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL - An Alternative Approach to Conventional Rational Drug Design
In this study we have calculated a 3D structure of apoptin and through modeling and docking approaches, we show its
interaction with Bcr-Abl oncoprotein and its downstream signaling components, following which we confirm some of the
newly-found interactions by biochemical methods. Bcr-Abl oncoprotein is aberrantly expressed in chronic myelogenous
leukaemia (CML). It has several distinct functional domains in addition to the Abl kinase domain. The SH3 and SH2 domains
cooperatively play important roles in autoinhibiting its kinase activity. Adapter molecules such as Grb2 and CrkL interact
with proline-rich region and activate multiple Bcr-Abl downstream signaling pathways that contribute to growth and
survival. Therefore, the oncogenic effect of Bcr-Abl could be inhibited by the interaction of small molecules with these
domains. Apoptin is a viral protein with well-documented cancer-selective cytotoxicity. Apoptin attributes such as SH2-like
sequence similarity with CrkL SH2 domain, unique SH3 domain binding sequence, presence of proline-rich segments, and
its nuclear affinity render the molecule capable of interaction with Bcr-Abl. Despite almost two decades of research, the
mode of apoptin’s action remains elusive because 3D structure of apoptin is unavailable. We performed in silico threedimensional
modeling of apoptin, molecular docking experiments between apoptin model and the known structure of Bcr-
Abl, and the 3D structures of SH2 domains of CrkL and Bcr-Abl. We also biochemically validated some of the interactions
that were first predicted in silico. This structure-property relationship of apoptin may help in unlocking its cancer-selective
toxic properties. Moreover, such models will guide us in developing of a new class of potent apoptin-like molecules with
greater selectivity and potency