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  • Title: ATP hydrolysis at one of the two sites in ABC transporters initiates transport related conformational transitions.
    Author: Gyimesi G, Ramachandran S, Kota P, Dokholyan NV, Sarkadi B, Hegedus T.
    Journal: Biochim Biophys Acta; 2011 Dec; 1808(12):2954-64. PubMed ID: 21840296.
    Abstract:
    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.
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