Biology subjects

Koh, A. F.

Publications and source records attributed to Koh, A. F..

2 recordsLinked to original sources

bioRxiv2023

Structural and quantum chemical basis for OCP-mediated quenching of phycobilisomes

Cyanobacteria employ large antenna complexes called phycobilisomes (PBS) for light harvesting. However, intense light triggers non-photochemical quenching, where the Orange Carotenoid Protein (OCP) binds to PBS, dissipating excess energy as heat. The mechanism of efficiently transferring energy from phycocyanobilins in PBS to canthaxanthin in OCP remains insufficiently understood. Using advanced cryogenic-electron microscopy, we unveiled the OCP-PBS complex structure at 1.6-2.1 [A] resolution, showcasing its inherent flexibility. Employing multiscale quantum chemistry, we disclosed the quenching mechanism. Identifying key protein residues, we clarified how canthaxanthins transition dipole moment in its lowest-energy dark state becomes large enough for efficient energy transfer from phycocyanobilins. Our energy transfer model offers a detailed understanding of the atomic determinants of light harvesting regulation and antenna architecture in cyanobacteria. One sentence summaryHigh-resolution cryo-EM structure of the OCP-PBS complex reveals intrinsic motions and enables the atomic simulation of the quenching mechanism

biophysics↗

bioRxiv2023

High-resolution cryo-electron microscopy of the human CDK-activating kinase for structure-based drug design

Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallisation has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 14 inhibitors at up to 1.8 [A] resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin- dependent kinase 7. Our data support a previously proposed mechanism contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. Additionally, our results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.

molecular biology↗