TY  - JOUR
AU  - Dmitrieva, Natalia
AU  - Gholami, Samira
AU  - Alleva, Claudia
AU  - Carloni, Paolo
AU  - Alfonso-Prieto, Mercedes
AU  - Fahlke, Christoph
TI  - Transport mechanism of DgoT, a bacterial homolog of SLC17 organic anion transporters
JO  - The EMBO journal
VL  - 43
IS  - 24
SN  - 0261-4189
CY  - [London]
PB  - Nature Publishing Group UK
M1  - FZJ-2025-01830
SP  - 6740 - 6765
PY  - 2024
AB  - The solute carrier 17 (SLC17) family contains anion transportersthat accumulate neurotransmitters in secretory vesicles, removecarboxylated monosaccharides from lysosomes, or extrude organicanions from the kidneys and liver.We combined classical moleculardynamics simulations, Markov state modeling and hybrid firstprinciples quantum mechanical/classical mechanical (QM/MM)simulations with experimental approaches to describe the transportmechanisms of a model bacterial protein, the D-galactonatetransporter DgoT, at atomic resolution. We found that protonationof D46 and E133 precedes galactonate binding and that substratebinding induces closure of the extracellular gate, with the conservedR47 coupling substrate binding to transmembrane helixmovement. After isomerization to an inward-facing conformation,deprotonation of E133 and subsequent proton transfer from D46 toE133 opens the intracellular gate and permits galactonate dissociationeither in its unprotonated form or after proton transferfrom E133. After release of the second proton, apo DgoT returns tothe outward-facing conformation. Our results provide a frameworkto understand how various SLC17 transport functions with distincttransport stoichiometries can be attained through subtle variationsin proton and substrate binding/unbinding.
LB  - PUB:(DE-HGF)16
DO  - DOI:10.1038/s44318-024-00279-y
UR  - https://juser.fz-juelich.de/record/1040302
ER  -