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Molecular mechanism of ligand recognition by membrane transport protein, Mhp1
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Simmons, Katie J., Jackson, Scott M., Brueckner, Florian, Patching, Simon G., Beckstein, Oliver, Ivanova, Ekaterina, Geng, Tian, Weyand, Simone, Drew, David, Lanigan, Joseph, Sharples, David J., Sansom, M. S. P. (Mark S. P.), Iwata, So, Fishwick, Colin W. G., Johnson, A. Peter, Cameron, Alexander and Henderson, P. J. F. (Peter J. F.) (2014) Molecular mechanism of ligand recognition by membrane transport protein, Mhp1. The EMBO Journal, 33 (16). pp. 1831-1844. doi:10.15252/embj.201387557
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Official URL: http://dx.doi.org/10.15252/embj.201387557
Abstract
The hydantoin transporter Mhp1 is a sodium-coupled secondary active transport protein of the nucleobase-cation-symport family and a member of the widespread 5-helix inverted repeat superfamily of transporters. The structure of Mhp1 was previously solved in three different conformations providing insight into the molecular basis of the alternating access mechanism. Here, we elucidate detailed events of substrate binding, through a combination of crystallography, molecular dynamics, site-directed mutagenesis, biochemical/biophysical assays, and the design and synthesis of novel ligands. We show precisely where 5-substituted hydantoin substrates bind in an extended configuration at the interface of the bundle and hash domains. They are recognised through hydrogen bonds to the hydantoin moiety and the complementarity of the 5-substituent for a hydrophobic pocket in the protein. Furthermore, we describe a novel structure of an intermediate state of the protein with the external thin gate locked open by an inhibitor, 5-(2-naphthylmethyl)-L-hydantoin, which becomes a substrate when leucine 363 is changed to an alanine. We deduce the molecular events that underlie acquisition and transport of a ligand by Mhp1.
| Item Type: | Journal Article | ||||||||
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| Subjects: | Q Science > QH Natural history | ||||||||
| Divisions: | Faculty of Science > Life Sciences (2010- ) | ||||||||
| Library of Congress Subject Headings (LCSH): | Hydantoin, Biological transport | ||||||||
| Journal or Publication Title: | The EMBO Journal | ||||||||
| Publisher: | Nature Publishing Group | ||||||||
| ISSN: | 0261-4189 | ||||||||
| Official Date: | 21 June 2014 | ||||||||
| Dates: |
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| Volume: | 33 | ||||||||
| Number: | 16 | ||||||||
| Page Range: | pp. 1831-1844 | ||||||||
| DOI: | 10.15252/embj.201387557 | ||||||||
| Status: | Peer Reviewed | ||||||||
| Publication Status: | Published | ||||||||
| Access rights to Published version: | Open Access | ||||||||
| Funder: | Seventh Framework Programme (European Commission) (FP7), European Commission (EC), Biotechnology and Biological Sciences Research Council (Great Britain) (BBSRC), Leverhulme Trust (LT), Wellcome Trust (London, England), Engineering and Physical Sciences Research Council (EPSRC) | ||||||||
| Grant number: | HEALTH-F4-2007-201924 (FP7), BB/C51725 (BBSRC), BB/G023425/1 (BBSRC), WT089809 (WT) |
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