G. Gyimesi, S. Ramachandran, P. Kota, N. V. Dokholyan, B. Sarkadi, and
T. Hegedus.
ATP hydrolysis at one of the two sites in ABC transporters
initiates transport related conformational transitions.
Biochimica et Biophysica Acta, 1808:2954-2964, 2011.
GYIM2011-AEZ
ABC transporters play important roles in all types of organisms by participating in
physiological and pathological processes. In order to modulate the function of ABC
transporters, detailed knowledge regarding their structure and dynamics is necessary.
Available structures of ABC proteins indicate three major conformations, a nucleotide-
bound “bottom-closed” state with the two nucleotide binding domains (NBDs) tightly
closed, and two nucleotide-free conformations, the “bottom-closed” and the “bottom-
open”, which differ in the extent of separation of the NBDs. However, it remains a question
how the widely open conformation should be interpreted, and whether hydrolysis at one of
the sites can drive conformational transitions while the NBDs remain in contact. To extend
our knowledge, we have investigated the dynamic properties of the Sav1866 transporter
using molecular dynamics (MD) simulations. We demonstrate that the replacement of one
ATP by ADP alters the correlated motion patterns of the NBDs and the transmembrane
domains (TMD). The results suggest that the hydrolysis of a single nucleotide could lead to
extracellular closure, driving the transport cycle. Essential dynamics analysis of simulations
suggests that single nucleotide hydrolysis can drive the system toward a “bottom-closed”
apo conformation similar to that observed in the structure of the MsbA transporter. We
also found significant structural instability of the “bottom-open” form of the transporters
in simulations. Our results suggest that ATP hydrolysis at one of the sites promotes
transport related conformational changes leading to the “bottom-closed” apo
conformation, which could thus be physiologically more relevant for describing the
structure of the apo state.
