|
ABC-transporter modeling
|
|
|
ABC (ATP-binding cassette) transporters are a large superfamily of integral membrane proteins that pump a variety of ligands through the cellular membranes. They include uptake and efflux pumps, which hydrolyse ATP to drive drug transport. Various ABC transporters play key roles in many hereditary diseases, such as cystic fibrosis, and confer resistance of bacterial and eukaryotic cells to antibiotics and numerous drugs applied for the treatment of infectious diseases, cancer, malaria, AIDS, etc. The transmembrane (TM) part of ABC transporters contains a polar channel formed by two homologous domains, each usually (with some exceptions) consisting of five (uptake transporters) or six (efflux transporters) TM alpha-helices. The determination of structures of the lipid flippase (Msba) with 6-alpha-helices (Chang & Roth, 2001) and of B12 uptake ABC-transporter (BtuCD) with 20-alpha-helices (Locher et al., 2002) seems to be a major breakthrough, because this allows 3D models of all other ABC transporters to be obtained. A comparison of such models with the numerous experimental data accumulated for MDR1, CFTR, and other ABC transporters would significantly advance our knowledge of their evolution, genetics, specificity of ligand binding, pumping mechanisms, association of NBD and transmembrane domains, and interactions with other domains and proteins. This could also aid the design of antagonists of the drug-resistance transporters, which would be of enormous practical importance.
|
Structure of lipid flippase Msba (Chang & Roth, 2001).
|
|
However, this goal can not be accomplished using the existing fold recognition and homology modeling programs due to several problems. First, many ABC transporters, including drug-resistance proteins, have no clear sequence homology in the TM region to the bacterial lipid flippase or BtuCD, and their folds remain uncertain The existing fold recognition programs have been developed using statistical rather than energetic approaches, and for water-soluble rather than membrane proteins. Second, even if the appropriate structural template would be defined, the existing homology modeling tools cannot reproduce variations in the spatial positions of TM helices in different ABC transporters. Third, the relative arrangement of two TM 6-alpha-helical domains may be variable in different representatives of the family, and this arrangement is expected to change during pumping of ligands through the membrane.
|
Structure of vitamin B12 transporter (Locher et al., 2002).
|
|
We are currently developing a new computational approach and software package MIMIC that will be applied to the large-scale modeling of TM domains from the ABC superfamily. All calculated models will be made publicly available through a planned ABC-3D database.
|
Collaborators Involved
|
|
|
David C. Dawson
, Ph.D. Professor and Chair, Department of Physiology & Pharmacology OHSU
|
Related Publications
|
|
Lomize AL, Reibarkh MY, Pogozheva ID
Interatomic potentials and solvation parameters from protein engineering data for buried residues.
Protein Sci., 11: 1984-2000 (2002)
|
External Funding
|
|
R21 GM61299, A. L. Lomize, PI
NIH/NIGM
Thermodynamic model of transmembrane alpha-bundles
|
|
|
|
|
