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The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion Binding from atomistic molecular dynamics simulations

The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion Binding from atomistic molecular dynamics simulations
The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion Binding from atomistic molecular dynamics simulations
The multidrug and toxic compound extrusion transporters extrude a wide variety of substrates out of both mammalian and bacterial cells via the electrochemical gradient of protons and cations across the membrane. The substrates transported by these proteins include toxic metabolites and antimicrobial drugs. These proteins contribute to multidrug resistance in both mammalian and bacterial cells and are therefore extremely important from a biomedical perspective. Although specific residues of the protein are known to be responsible for the extrusion of solutes, mechanistic details and indeed structures of all the conformational states remain elusive. Here, we report the first, to our knowledge, simulation study of the recently resolved x-ray structure of the multidrug and toxic compound extrusion transporter, NorM from Neisseria gonorrhoeae (NorM_NG). Multiple, atomistic simulations of the unbound and bound forms of NorM in a phospholipid lipid bilayer allow us to identify the nature of the drug-protein/ion-protein interactions, and secondly determine how these interactions contribute to the conformational rearrangements of the protein. In particular, we identify the molecular rearrangements that occur to enable the Na+ ion to enter the cation-binding cavity even in the presence of a bound drug molecule. These include side chain flipping of a key residue, GLU-261 from pointing toward the central cavity to pointing toward the cation binding side when bound to a Na+ ion. Our simulations also provide support for cation binding in the drug-bound and apo states of NorM_NG.
0006-3495
460-468
Leung, Yuk Ming
20384feb-566e-4022-946e-2540053fb000
Holdbrook, Daniel A.
d114c018-fb42-4a49-9b50-f7739feb75f5
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394
Leung, Yuk Ming
20384feb-566e-4022-946e-2540053fb000
Holdbrook, Daniel A.
d114c018-fb42-4a49-9b50-f7739feb75f5
Piggot, Thomas J.
75829b71-d73b-43d1-b24f-3e70c2c4d0c8
Khalid, Syma
90fbd954-7248-4f47-9525-4d6af9636394

Leung, Yuk Ming, Holdbrook, Daniel A., Piggot, Thomas J. and Khalid, Syma (2014) The NorM MATE transporter from N. gonorrhoeae: insights into drug and ion Binding from atomistic molecular dynamics simulations. Biophysical Journal, 107 (2), 460-468. (doi:10.1016/j.bpj.2014.06.005).

Record type: Article

Abstract

The multidrug and toxic compound extrusion transporters extrude a wide variety of substrates out of both mammalian and bacterial cells via the electrochemical gradient of protons and cations across the membrane. The substrates transported by these proteins include toxic metabolites and antimicrobial drugs. These proteins contribute to multidrug resistance in both mammalian and bacterial cells and are therefore extremely important from a biomedical perspective. Although specific residues of the protein are known to be responsible for the extrusion of solutes, mechanistic details and indeed structures of all the conformational states remain elusive. Here, we report the first, to our knowledge, simulation study of the recently resolved x-ray structure of the multidrug and toxic compound extrusion transporter, NorM from Neisseria gonorrhoeae (NorM_NG). Multiple, atomistic simulations of the unbound and bound forms of NorM in a phospholipid lipid bilayer allow us to identify the nature of the drug-protein/ion-protein interactions, and secondly determine how these interactions contribute to the conformational rearrangements of the protein. In particular, we identify the molecular rearrangements that occur to enable the Na+ ion to enter the cation-binding cavity even in the presence of a bound drug molecule. These include side chain flipping of a key residue, GLU-261 from pointing toward the central cavity to pointing toward the cation binding side when bound to a Na+ ion. Our simulations also provide support for cation binding in the drug-bound and apo states of NorM_NG.

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Published date: 15 July 2014
Organisations: Chemistry

Identifiers

Local EPrints ID: 369443
URI: http://eprints.soton.ac.uk/id/eprint/369443
ISSN: 0006-3495
PURE UUID: 7fadf72d-dffc-44a1-ab3d-ce4ff7c3865d
ORCID for Syma Khalid: ORCID iD orcid.org/0000-0002-3694-5044

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Date deposited: 01 Oct 2014 13:41
Last modified: 20 Jul 2019 00:51

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