EPFL BioE Talks SERIES "Activation and Inhibition of an Unusual G Protein-Coupled Receptor"
Event details
| Date | 27.11.2023 |
| Hour | 16:00 › 17:00 |
| Speaker | Prof. Andrew Kruse, Harvard Medical School, Boston, MA (USA) |
| Location | Online |
| Category | Conferences - Seminars |
| Event Language | English |
WEEKLY EPFL BIOE TALKS SERIES
Abstract:
The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of a low-density lipoprotein receptor class A (LDLa) module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. We determined the cryo-electron microscopy structure of active-state human RXFP1 bound to a single-chain analog of the endogenous agonist relaxin-2 and the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition by the ectodomain. More recently, we have determined the structure of RXFP1 in an inactive state and an active-state structure of RXFP1 bound to a small-molecule agonist. Our results explain how this unusual GPCR functions, and have enabled rational engineering of a long-acting agonist that is in clinical development.
Bio:
Dr. Kruse is a Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. His research focuses on the structure and function of transmembrane receptors, using a combination of biophysical and cell biological approaches. Research in the Kruse lab also makes extensive use of combinatorial protein engineering methods such as yeast surface display of single-domain antibody fragments.
Dr. Kruse began his independent career as an Assistant Professor at Harvard Medical School in 2014. Key research accomplishments include defining the structural basis for agonist action at the angiotensin II type 1 receptor and other G protein-protein coupled receptors (GPCRs), cloning the sigma-2 receptor, and determining the first structure of a tetraspanin protein and showing how it regulates B cell activation. The Kruse lab also developed a single-domain antibody fragment discovery platform. Dr. Kruse is a co-founder of Tectonic Therapeutic, a biotechnology company, and the Institute for Protein Innovation, a non-profit research organization. He has received awards including an Amgen Young Investigator Award (2019), an Alfred P. Sloan Research Fellowship (2017), a Vallee Scholars Award (2016), and an NIH Director’s Early Independence Award (2015). He received B.S. degrees in Mathematics and Biochemistry from the University of Minnesota in 2009, and completed a Ph.D. in Structural Biology at Stanford University in 2014, where he trained with Dr. Brian Kobilka.
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
Abstract:
The relaxin family peptide receptor 1 (RXFP1) is the receptor for relaxin-2, an important regulator of reproductive and cardiovascular physiology. RXFP1 is a multi-domain G protein-coupled receptor (GPCR) with an ectodomain consisting of a low-density lipoprotein receptor class A (LDLa) module and leucine-rich repeats. The mechanism of RXFP1 signal transduction is clearly distinct from that of other GPCRs, but remains very poorly understood. We determined the cryo-electron microscopy structure of active-state human RXFP1 bound to a single-chain analog of the endogenous agonist relaxin-2 and the heterotrimeric Gs protein. Evolutionary coupling analysis and structure-guided functional experiments reveal that RXFP1 signals through a mechanism of autoinhibition by the ectodomain. More recently, we have determined the structure of RXFP1 in an inactive state and an active-state structure of RXFP1 bound to a small-molecule agonist. Our results explain how this unusual GPCR functions, and have enabled rational engineering of a long-acting agonist that is in clinical development.
Bio:
Dr. Kruse is a Professor of Biological Chemistry and Molecular Pharmacology at Harvard Medical School. His research focuses on the structure and function of transmembrane receptors, using a combination of biophysical and cell biological approaches. Research in the Kruse lab also makes extensive use of combinatorial protein engineering methods such as yeast surface display of single-domain antibody fragments.
Dr. Kruse began his independent career as an Assistant Professor at Harvard Medical School in 2014. Key research accomplishments include defining the structural basis for agonist action at the angiotensin II type 1 receptor and other G protein-protein coupled receptors (GPCRs), cloning the sigma-2 receptor, and determining the first structure of a tetraspanin protein and showing how it regulates B cell activation. The Kruse lab also developed a single-domain antibody fragment discovery platform. Dr. Kruse is a co-founder of Tectonic Therapeutic, a biotechnology company, and the Institute for Protein Innovation, a non-profit research organization. He has received awards including an Amgen Young Investigator Award (2019), an Alfred P. Sloan Research Fellowship (2017), a Vallee Scholars Award (2016), and an NIH Director’s Early Independence Award (2015). He received B.S. degrees in Mathematics and Biochemistry from the University of Minnesota in 2009, and completed a Ph.D. in Structural Biology at Stanford University in 2014, where he trained with Dr. Brian Kobilka.
Zoom link (with one-time registration for the whole series) for attending remotely: https://go.epfl.ch/EPFLBioETalks
Instructions for 1st-year Ph.D. students who are under EDBB’s mandatory seminar attendance rule:
IF you are not attending in-person in the room, please make sure to
- send D. Reinhard a note before noon on seminar day, informing that you plan to attend the talk online, and
- be signed in on Zoom with a recognizable user name (not a pseudonym making it difficult or impossible to be identified).
Practical information
- Informed public
- Registration required
Organizer
Contact
- Institute of Bioengineering (IBI), Dietrich REINHARD