Transporting drugs and protons: E. coli ATP synthase and human OCT1.

Presenter: Dr. Alastair Stewart
Victor Chang Cardiac Research Institute, Sydney

In this seminar Alastair will present recent cryo-EM studies on two different membrane proteins:
(i) F1Fo ATP synthase, a biological rotary generator essential for cellular energy, utilises proton flow through its membrane motor to drive rotation and catalyse ATP production in the soluble F 1 motor. Using cryo-EM, rotational sub-states and torsional flexibilities have been revealed, enhancing the understanding of its catalytic mechanism and regulatory domains.
(ii) OCT1 mediates the hepatic uptake of various metabolites and drugs, with genetic variations affecting their efficacy and safety. Using cryo-EM, structures of OCT1 have been solved in outward and inward states, bound to a series of drugs. Combined with functional assays, these structures reveal OCT1’s broad substrate recognition and provide insights into its substrate translocation mechanism, highlighting the role of hydrophobic gates and charge neutralisation on drug binding.

About Dr. Stewart: Alastair is a laboratory head at the Victor Chang Cardiac Research Institute in Sydney Australia. Throughout his career he has used a complementary spectrum of structural and biochemical methods to unravel the function of protein complexes important in biomedicine. Alastair embarked on his scientific journey at the University of Cambridge, where he read the Natural Sciences Tripos. He subsequently moved to Sydney to pursue a PhD focused on deciphering the mechanism of ATP synthase. Following his doctoral studies Alastair undertook a brief postdoctoral fellowship at the University of Sydney, delving into the regulation of chromatin by long non-coding RNAs, before setting up his independent research group at the Victor Chang Cardiac Research Institute in 2016. Alastair has been the recipient of three consecutive fellowships from the National Health and Medical Research Council, most recently being awarded the Commonwealth Health Minister's Award for Excellence in Health and Medical Research for the highest ranked Emerging Leader Investigator Grant in 2023.

Chair: Mayada Mazher, CCeMMP ICHDR, UoM/Bio21 Node