alternatingaccess

Alternating access is a mechanistic model for how many transporter proteins move substrates across cell membranes. In this model, the substrate-binding site of a transporter is alternately exposed to the outside of the cell and to the cytoplasm. When the site faces the outside, substrate binds; a conformational change occludes the binding site and reorients the transporter so the site faces inward, allowing release; a subsequent change restores the original outward-facing state, ready to begin another cycle. Importantly, the binding site is never open to both sides at once, preventing a continuous leak.

The process is driven by conformational changes that are coupled to energy sources. Secondary active transporters use ion gradients or chemiosmotic energy to drive the cycle; facilitated diffusion transporters proceed down substrates' gradients without direct energy expenditure; ATP-powered transporters (ABC transporters) couple ATP hydrolysis to alternating access. The general framework accommodates multiple structural solutions, including rocker-switch domains where alternating transmembrane helices pivot, and elevator or gate mechanisms found in different families.

Evidence comes from kinetic studies and structural snapshots showing outward-facing, inward-facing, and occluded conformations in various transporters such as those in the major facilitator superfamily (MFS) and beyond. The alternating access model explains how transporters achieve directionality and substrate specificity while maintaining membrane integrity.

Impact: the model provides a unifying description for diverse transporters and informs research in physiology, pharmacology, and drug design, where transporter function can influence absorption, distribution, and resistance.