Mechanism of Substrate Translocation in an Alternating Access Transporter

Naomi R. Latorraca, Nathan M. Fastman, A.J. Venkatakrishnan, Wolf B. Frommer, Ron O. Dror, Liang Feng
2017 Cell  
Transporters shuttle molecules across cell membranes by alternating among distinct conformational states. Fundamental questions remain about how transporters transition between states and how such structural rearrangements regulate substrate translocation. Here we capture the translocation process by crystallography and unguided molecular dynamics simulations, providing an atomic-level description of alternating access transport. Simulations of a SWEET-family transporter initiated from an
more » ... d-open, glucose-bound structure reported here spontaneously adopt occluded and inward-open conformations. Strikingly, these conformations match crystal structures, including our inward-open structure. Mutagenesis experiments further validate simulation predictions. Our results reveal that state transitions are driven by favorable interactions formed upon closure of extracellular and intracellular "gates" and by an unfavorable transmembrane helix configuration when both gates are closed. This mechanism leads to tight
doi:10.1016/j.cell.2017.03.010 pmid:28340354 pmcid:PMC5557413 fatcat:d2dongtdgvdvzpfyig7sgujk3m