Structural diversity of ABC transporters

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Abstract

ATP-binding cassette (ABC) transporters form a large superfamily of ATP-dependent protein complexes that mediate transport of a vast array of substrates across membranes. The 14 currently available structures of ABC transporters have greatly advanced insight into the transport mechanism and revealed a tremendous structural diversity. Whereas the domains that hydrolyze ATP are structurally related in all ABC transporters, the membrane-embedded domains, where the substrates are translocated, adopt four different unrelated folds. Here, we review the structural characteristics of ABC transporters and discuss the implications of this structural diversity for mechanistic diversity.

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Most cited references 78

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Simple allosteric model for membrane pumps.

O Jardetzky (1966)

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P-glycoprotein: from genomics to mechanism.

Suresh Ambudkar, Chava Kimchi-Sarfaty, Zuben Sauna … (2003)

Resistance to chemically different natural product anti-cancer drugs (multidrug resistance, or MDR) results from decreased drug accumulation, resulting from expression of one or more ATP-dependent efflux pumps. The first of these to be identified was P-glycoprotein (P-gp), the product of the human MDR1 gene, localized to chromosome 7q21. P-gp is a member of the large ATP-binding cassette (ABC) family of proteins. Although its crystallographic 3-D structure is yet to be determined, sequence analysis and comparison to other ABC family members suggest a structure consisting of two transmembrane (TM) domains, each with six TM segments, and two nucleotide-binding domains. In the epithelial cells of the gastrointestinal tract, liver, and kidney, and capillaries of the brain, testes, and ovaries, P-gp acts as a barrier to the uptake of xenobiotics, and promotes their excretion in the bile and urine. Polymorphisms in the MDR1 gene may affect the pharmacokinetics of many commonly used drugs, including anticancer drugs. Substrate recognition of many different drugs occurs within the TM domains in multiple-overlapping binding sites. We have proposed a model for how ATP energizes transfer of substrates from these binding sites on P-gp to the outside of the cell, which accounts for the apparent stoichiometry of two ATPs hydrolysed per molecule of drug transported. Understanding of the biology, genetics, and biochemistry of P-gp promises to improve the treatment of cancer and explain the pharmacokinetics of many commonly used drugs.

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Refined structures of mouse P-glycoprotein

Jingzhi Li, Kimberly Jaimes, Stephen G. Aller (2013)

The recently determined C. elegans P-glycoprotein (Pgp) structure revealed significant deviations compared to the original mouse Pgp structure, which suggested possible misinterpretations in the latter model. To address this concern, we generated an experimental electron density map from single-wavelength anomalous dispersion phasing of an original mouse Pgp dataset to 3.8 Å resolution. The map exhibited significantly more detail compared to the original MAD map and revealed several regions of the structure that required de novo model building. The improved drug-free structure was refined to 3.8 Å resolution with a 9.4 and 8.1% decrease in R work and R free, respectively, (R work = 21.2%, R free = 26.6%) and a significant improvement in protein geometry. The improved mouse Pgp model contains ∼95% of residues in the favorable Ramachandran region compared to only 57% for the original model. The registry of six transmembrane helices was corrected, revealing amino acid residues involved in drug binding that were previously unrecognized. Registry shifts (rotations and translations) for three transmembrane (TM)4 and TM5 and the addition of three N-terminal residues were necessary, and were validated with new mercury labeling and anomalous Fourier density. The corrected position of TM4, which forms the frame of a portal for drug entry, had backbone atoms shifted >6 Å from their original positions. The drug translocation pathway of mouse Pgp is 96% identical to human Pgp and is enriched in aromatic residues that likely play a collective role in allowing a high degree of polyspecific substrate recognition. PDB Code(s): 4M1M, 4M2S, 4M2T

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Author and article information

Journal

Journal ID (nlm-ta): J Gen Physiol

Journal ID (iso-abbrev): J. Gen. Physiol

Journal ID (hwp): jgp

Journal ID (publisher-id): jgp

Title: The Journal of General Physiology

Publisher: The Rockefeller University Press

ISSN (Print): 0022-1295

ISSN (Electronic): 1540-7748

Publication date (Print): April 2014

Volume: 143

Issue: 4

Pages: 419-435

Affiliations

Department of Biochemistry, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, 9747 AG Groningen, Netherlands

Author notes

Correspondence to Dirk Jan Slotboom: d.j.slotboom@ 123456rug.nl

J. ter Beek and A. Guskov contributed equally to this paper.

J. ter Beek’s present address is Dept. of Biochemistry and Biophysics, University of Stockholm, 114 18 Stockholm, Sweden.

Article

Publisher ID: 201411164

DOI: 10.1085/jgp.201411164

PMC ID: 3971661

PubMed ID: 24638992

SO-VID: 7ac5528a-6614-4bc1-9793-d04ca7a9cc95

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This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

Structural diversity of ABC transporters

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Most cited references 78

Simple allosteric model for membrane pumps.

P-glycoprotein: from genomics to mechanism.

Refined structures of mouse P-glycoprotein

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