Structural characterization of two metastable ATP-bound states of P-glycoprotein

O'Mara, Megan L. and Mark, Alan E. (2014) Structural characterization of two metastable ATP-bound states of P-glycoprotein. PLoS One, 9 3: e91916.1-e91916.14. doi:10.1371/journal.pone.0091916

Author O'Mara, Megan L.
Mark, Alan E.
Title Structural characterization of two metastable ATP-bound states of P-glycoprotein
Journal name PLoS One   Check publisher's open access policy
ISSN 1932-6203
Publication date 2014-03-14
Sub-type Article (original research)
DOI 10.1371/journal.pone.0091916
Open Access Status DOI
Volume 9
Issue 3
Start page e91916.1
End page e91916.14
Total pages 14
Editor Anthony George
Place of publication San Francisco, CA, United States
Publisher Public Library of Science
Language eng
Formatted abstract
ATP Binding Cassette (ABC) transporters couple the binding and hydrolysis of ATP to the transport of substrate molecules across the membrane. The mechanism by which ATP binding and/or hydrolysis drives the conformational changes associated with substrate transport has not yet been characterized fully. Here, changes in the conformation of the ABC export protein P-glycoprotein on ATP binding are examined in a series of molecular dynamics simulations. When one molecule of ATP is placed at the ATP binding site associated with each of the two nucleotide binding domains (NBDs), the membrane-embedded P-glycoprotein crystal structure adopts two distinct metastable conformations. In one, each ATP molecule interacts primarily with the Walker A motif of the corresponding NBD. In the other, the ATP molecules interacts with both Walker A motif of one NBD and the Signature motif of the opposite NBD inducing the partial dimerization of the NBDs. This interaction is more extensive in one of the two ATP binding site, leading to an asymmetric structure. The overall conformation of the transmembrane domains is not altered in either of these metastable states, indicating that the conformational changes associated with ATP binding observed in the simulations in the absence of substrate do not lead to the outward-facing conformation and thus would be insufficient in themselves to drive transport. Nevertheless, the metastable intermediate ATP-bound conformations observed are compatible with a wide range of experimental cross-linking data demonstrating the simulations do capture physiologically important conformations. Analysis of the interaction between ATP and its cofactor Mg2+ with each NBD indicates that the coordination of ATP and Mg2+ differs between the two NBDs. The role structural asymmetry may play in ATP binding and hydrolysis is discussed. Furthermore, we demonstrate that our results are not heavily influenced by the crystal structure chosen for initiation of the simulations.
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ

Version Filter Type
Citation counts: TR Web of Science Citation Count  Cited 10 times in Thomson Reuters Web of Science Article | Citations
Scopus Citation Count Cited 12 times in Scopus Article | Citations
Google Scholar Search Google Scholar
Created: Fri, 21 Mar 2014, 21:08:39 EST by Mrs Louise Nimwegen on behalf of School of Chemistry & Molecular Biosciences