Description
Flyer: Dickerson Lecture Flyer – Robert M. Stroud
Title: “Caught in the Act! – Building the Wall!”
Abstract: From the atomic structure of the first protein, Myoglobin in which Richard Dickerson played the key role(1), proteins were necessarily purified from large animals. Now complex machines can be ‘tagged’ and purified endogenously from cells growing under normal conditions(2), revealing their endogenous partnerships, natural substrates, and reactions as if trapped ‘in action’. The mycolic acid layer of the Mycobacterium tuberculosis cell wall is essential for viability and virulence, and the enzymes responsible for its synthesis are therefore targets for antimycobacterial drug development. Polyketide synthase 13 (Pks13) performs the key essential final condensation of mycolic acids. Structures determined by cryogenic electron microscopy of dimeric multi-enzyme Pks13 purified from mycobacteria, are captured with native endogenous long-chain fatty acid substrates. Structures define the ketosynthase (KS), linker domains, and acyltransferase (AT) domains at 1.8 Å resolution, and show two alternate locations of the N-terminal acyl carrier protein that delivers substrate from a fatty acid synthase to the KS domain. Other domains, visible only at low resolution, are flexible relative to the KS-AT core. These structures, together with cross linking and integrative modeling suggest intermediate states on the pathway to mycolic acid synthesis(3).