The Gordon Hammes Lectureship Award recognizes and honors an individual whose scientific contributions have had a major impact on research across all of biological chemistry. The winner of this year’s award, Monash University’s Dr. Patrick Sexton, will present the Gordon Hammes Lecture during the ACS Spring 2023 Meeting & Exposition March 26 – 30 in Indianapolis, IN.
“Sexton’s work has great impact on our understanding of ligand-GPCR interactions, how these interactions induce receptor activation, and how receptor dynamics contribute to the sophisticated and multi-layered chemistry that characterizes GPCRs. He is a terrific choice for the Hammes Lectureship Award,” said Biochemistry Editor-in-Chief Alanna Schepartz.
Read a brief interview with Gordon Hammes Lectureship Award Winner, Dr. Patrick Sexton
What do you consider to be the most important advances in biochemistry in the past five years?
One of the standouts would be the speed with which we have seen the development of diverse and highly efficacious vaccines for Covid. This has been a great example of the implementation of high-throughput structural biology, particularly cryo-EM, to inform vaccine design and the value of rapid open access publishing to address a critical public health question. It also saw the emergence of mRNA vaccines as mainstream medicines, and this is likely to be transformative for future vaccine development. Beyond this has been the advent of impressive computational approaches to protein structure prediction and the accessibility of these tools to the research community. From a researcher studying membrane proteins, the continued evolution of cryo-EM coupled with ongoing developments in protein expression, and purification/reconstitution, along with biochemical tools and approaches to attain high-resolution structural information on membrane proteins in multiple biochemically and pharmacologically important states has been one of the tremendous advances over the last 5 years. This has provided near atomic level detail on numerous hitherto intractable proteins/protein states. Moreover, we are increasingly seeing integrated techniques for studying the conformational dynamics of membrane proteins that are critically important to understanding how they function and how they are modulated by different classes of drugs. Finally, for linkage of structure to function, the ongoing development of new tools that enable the study of complex biochemical systems in live cells, including proximity proteomics, and numerous biophysical methods such as FRET and BRET that are being applied in increasingly high-throughput ways to enable time- and spatially-resolved understanding of cellular events such as receptor signalling, trafficking and regulation has also been an important advance.
Can you give us a short overview of the research you are currently undertaking?
My laboratory, co-led by myself and Denise Wootten, studies G protein-coupled receptors (GPCRs), the largest family of cell surface membrane proteins, with a particular focus on a subfamily of these receptors that bind to physiologically important peptide hormones. The laboratory has research that spans structure elucidation through biochemical and pharmacology assays of receptor function, to animal models of disease, which we use to understand the chemical biology and pharmacology of allosteric ligands and biased agonists, and the integration of this insight with high-resolution structure and dynamics to understand peptide and small molecule drug action. We were among the first to apply single particle cryo-EM to determine high-resolution structures of GPCRs, particularly for active-state structures that were extremely challenging by x-ray crystallography, including the development of modified G proteins to improve stabilisation of GPCR-G protein complexes that can be applied to multiple G protein subtypes. We have applied these methods to study both peptide and small molecule drug binding to GPCRs and to gain insight into the mechanism of activation for class B peptide hormone GPCRs. Of course, GPCRs are conformationally dynamic proteins and we have been using recent advances in analysis of cryo-EM data to directly visualise conformational ensembles that are captured during vitrification. This has been critical to gain insight into the mechanistic basis for distinct ligand pharmacology that may not be revealed in high-resolution consensus cryo-EM maps. Increasingly, we are using integrated approaches to probe dynamics of GPCR function, such as the combination of cryo-EM and HDX-MS, often supported by molecular dynamics simulations, to broaden temporal and/or spatial resolution that is going to be key to linking molecular changes in proteins to observed function in biochemical, biophysical and pharmacological assays.
What advice would you give to students who aspire to be where you are now?
The first piece of advice is to be excited by what you do. We are very privileged as our work enables us to be the first to discover aspects of how proteins/cells/integrated systems function. Whether these are small insights or those that change the way we need to think they are all important in evolving our fields. It is important to not lose sight of this. If you can’t be excited by your science, it is probably not the best career choice.
The second would be to foster and build collaborations and partnerships. I have been very fortunate to work with some amazing scientists and there is great benefit in bringing together people with different backgrounds, ideas and expertise. This is important for all of our science, but long-term partnerships built on trust and shared vision have been the backbone of my career.