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Reference: Lee, J, Daniels, V, Sands, ZA et al., (2015). Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis. PloS one, 10 (2), e0116589.Citable link to this page:

 

Exploring the interaction of SV2A with racetams using homology modelling, molecular dynamics and site-directed mutagenesis.

Abstract: The putative Major Facilitator Superfamily (MFS) transporter, SV2A, is the target for levetiracetam (LEV), which is a successful anti-epileptic drug. Furthermore, SV2A knock out mice display a severe seizure phenotype and die after a few weeks. Despite this, the mode of action of LEV is not known at the molecular level. It would be extremely desirable to understand this more fully in order to aid the design of improved anti-epileptic compounds. Since there is no structure for SV2A, homology modelling can provide insight into the ligand-binding site. However, it is not a trivial process to build such models, since SV2A has low sequence identity to those MFS transporters whose structures are known. A further level of complexity is added by the fact that it is not known which conformational state of the receptor LEV binds to, as multiple conformational states have been inferred by tomography and ligand binding assays or indeed, if binding is exclusive to a single state. Here, we explore models of both the inward and outward facing conformational states of SV2A (according to the alternating access mechanism for MFS transporters). We use a sequence conservation analysis to help guide the homology modelling process and generate the models, which we assess further with Molecular Dynamics (MD). By comparing the MD results in conjunction with docking and simulation of a LEV-analogue used in radioligand binding assays, we were able to suggest further residues that line the binding pocket. These were confirmed experimentally. In particular, mutation of D670 leads to a complete loss of binding. The results shed light on the way LEV analogues may interact with SV2A and may help with the on-going design of improved anti-epileptic compounds.

Peer Review status:Peer reviewedPublication status:PublishedVersion:Publisher's versionNotes:Copyright © 2015 Lee et al. This is an open accessarticle distributed under the terms of the CreativeCommons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.

Bibliographic Details

Publisher: Public Library of Science

Publisher Website: http://www.plos.org/

Journal: PloS onesee more from them

Publication Website: http://www.plosone.org/

Issue Date: 2015-1

pages:e0116589Identifiers

Urn: uuid:b7b4a1f1-0ade-4d77-8374-6c5389b21bcf

Source identifier: 508050

Eissn: 1932-6203

Doi: https://doi.org/10.1371/journal.pone.0116589

Issn: 1932-6203 Item Description

Type: Journal article;

Language: eng

Version: Publisher's versionKeywords: sequence alignment biochemical simulations simulation and modeling multiple alignment calculation binding analysis drug interactions membrane proteins BLAST algorithm Tiny URL: pubs:508050

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Autor: Lee, J - institutionUniversity of Oxford Oxford, MSD, Biochemistry fundingBiotechnology and Biological Sciences Research Council

Fuente: https://ora.ox.ac.uk/objects/uuid:b7b4a1f1-0ade-4d77-8374-6c5389b21bcf



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