Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL - An Alternative Approach to Conventional Rational Drug Design

↓ Direkt till sidans innehåll
↓ Direkt till sidans sekundära innehåll (sidomenyn)

Search: WFRF:(Stetefeld Joerg) > Modeling of Molecul...

Details
MARC

Panigrahi, SoumyaLerner Research Institute, Cleveland, Ohio, USA (author)

Modeling of Molecular Interaction between Apoptin, BCR-Abl and CrkL - An Alternative Approach to Conventional Rational Drug Design

Article/chapterEnglish2012

Publisher, publication year, extent ...

2012-01-10
Public Library of Science,2012
electronicrdacarrier

Numbers

LIBRIS-ID:oai:DiVA.org:liu-76543
https://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-76543URI
https://doi.org/10.1371/journal.pone.0028395DOI

Supplementary language notes

Language:English
Summary in:English

Part of subdatabase

SwePubSwePub

Classification

Subject category:ref swepub-contenttype
Subject category:art swepub-publicationtype

Notes

Funding Agencies|Memorial University||College of the North Atlantic, Clarenville Campus||Canada Research Chair program||Linkoping University, Integrative Regenerative Medicine Center (IGEN)||Cancerfonden|CAN 2011/521|
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 (CIVIL). 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 apoptins action remains elusive because 3D structure of apoptin is unavailable. We performed in silico three-dimensional 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 silica. 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.

Subject headings and genre

MEDICINE
MEDICIN

Added entries (persons, corporate bodies, meetings, titles ...)

Stetefeld, JoergUniversity of Manitoba, Winnipeg, Canada (author)
Jangamreddy, Jaganmohan R.Linköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)jagre79 (author)
Mandal, SomaUniversity of Manitoba, Winnipeg, Canada (author)
Mandal, Sanat K.Memorial University of Newfoundland, Canada (author)
Los, Marek JanLinköpings universitet,Cellbiologi,Hälsouniversitetet(Swepub:liu)marlo14 (author)
Lerner Research Institute, Cleveland, Ohio, USAUniversity of Manitoba, Winnipeg, Canada (creator_code:org_t)

Related titles

In:PLOS ONE: Public Library of Science7:1, s. 6-201932-6203

Internet link

Find in a library

PLOS ONE (Search for host publication in LIBRIS)

To the university's database

Find more in SwePub

By the author/editor: Panigrahi, Soumy ...; Stetefeld, Joerg; Jangamreddy, Jag ...; Mandal, Soma; Mandal, Sanat K.; Los, Marek Jan

Articles in the publication: PLOS ONE

By the university: Linköping University

Search outside SwePub

Extend your search to:: Google; Google Book Search; Google Scholar

Kungliga biblioteket hanterar dina personuppgifter i enlighet med EU:s dataskyddsförordning (2018), GDPR. Läs mer om hur det funkar här.
Så här hanterar KB dina uppgifter vid användning av denna tjänst.

LIBRIS.kb.se