Subsequent projects

Prof. Dr. Peter Gmeiner
of Erlangen-Nuremberg
Chair of Pharmaceutical Chemistry

Prof. Dr. Brian Kobilka
Stanford University
Molecular and Cellular Physiology and Medicine

Structural and functional properties of G protein coupled receptors

Monoaminergic receptors including a number of adrenergic and dopaminergic subtypes are known as target proteins for CNS- and cardiovascular-active drugs and serve as model systems for understanding the structure, cell biology, and physiology of GPCR-ligand complexes. Brian Koblika’s lab at Stanford has developed biophysical methodology to monitor the structure and ligand-induced conformational changes of GPCRs. Peter Gmeiner’s group in Erlangen has substantial experience in the design and organic synthesis of novel, highly specific GPCR agonists and antagonists. The collaborative investigations resulted in a crystal structure of the first agonist-bound GPCR. Using crystallography as a tool to develop medicinal chemistry of a given GPCR, collaboration between the Bavarian and the Californian research group will lead to novel insights into structure activity relationships that will be transferred to related receptor ligand systems.


Primary project: Functional properties of G protein coupled receptors


Final Report

Our initial collaborative investigations resulted in an evolutionary process leading to covalent catecholamine analogs. The compounds that were developed in the lab of Peter Gmeiner at Friedrich-Alexander University showed covalent binding to the receptor and the functional properties of full agonists. After careful functional studies, crystallization experiments in the laboratory of Brian Kobilka at Stanford University led to crystal structures of agonist-bound GPCRs. The concept of our collaboration with the laboratory of Brian Kobilka takes advantage of the complementarity of expertise between both groups. Structural biology and medicinal chemistry work together, in order to develop high resolution X-ray crystal structures of therapeutically relevant G-protein coupled receptors bound to highly specific ligands. Subsequently, we attempt to use those structures for the design of novel drug candidates.

X-ray crystallography is also of great interest for lead compound optimizations and drug discovery, because a rational structural basis facilitates a more efficient approach to new drug candidates. Thus, we intend to establish GPCR crystallography also in my lab in Erlangen. Together with Dr. Dorothee Möller in my lab, we have chosen the dopamine D3 receptor subtype as a model receptor that has been crystallized already, to obtain new high-resolution structures with specific ligands to be developed in my laboratory in Erlangen. Using crystallography as a tool to develop medicinal chemistry of a given GPCR, this will lead to novel insights into structure activity relationships that may be transferred to related receptor ligand systems. Brian Kobilka strongly supported our concept and helps us to establish the methodology in my laboratory at FAU. Because the experience of his laboratory is constitutive for the success of such an approach (only a very few laboratories worldwide are able to crystallize GPCRs so far), Dr. Möller performed a research stay at Stanford. In tight contact with the Kobilka lab, she currently works on the purification of the receptor protein in my lab. We are very confident that the project will give us crystal structures of interesting GPCR-ligand complexes in due course.

Thanks to the initiation by BaCaTeC, our collaboration is funded by the National Institutes of Health providing my laboratory with grant money for further scientific investigations in the field of medicinal chemistry of G-protein coupled receptors. We are currently working on the proposal of a second NIH-funded grant application that we plan to submit in June 2018.

The following publications are related to the funded project:

  1. Structure-Based Design and Discovery of New M2 Receptor Agonists. Inbar Fish, Anne Stoessel, Katrin Eitel, Celine Valant, Sabine Albold, Harald Huebner, Dorothee Moeller, Mary J. Clark, Roger K. Sunahara, Arthur Christopoulos, Brian K. Shoichet, Peter Gmeiner. J. Med. Chem. 2017, 60, 9239-9250.
    (Prof. Kobilka is not a co-author, because he was only slightly involved. We joint work with the colleagues Sunahara (UCSD) and Shoichet (UCSF) has been facilitated by the stay of Dr. Dorothee Möller in California funded by BaCaTeC.)
  2. Structure-based discovery of opioid analgesics with reduced side effects. Aashish Manglik, Henry Lin, Dipendra K. Aryal, John D. McCorvy, Daniela Dengler, Gregory Corder, Anat Levit, Ralf C. Kling, Viachaslau Bernat, Harald Huebner, Xi-Ping Huang, Maria F. Sassano, Patrick M. Giguere, Stefan Loeber, Da Duan, Gregory Scherrer, Brian K. Kobilka, Peter Gmeiner, Bryan L. Roth, Brian K. Shoichet. Nature 2016, 537, 185-190.
  3. Structural insights into mu-opioid receptor activation. Weijiao Huang, Aashish Manglik, A. J. Venkatakrishnan, Toon Laeremans, Evan N. Feinberg, Adrian L. Sanborn, Hideaki E. Kato, Kathryn E. Livingston, Thor S. Thorsen, Ralf C. Kling, Sebastien Granier, Peter Gmeiner, Stephen M. Husbands, John R. Traynor, William I. Weis, Jan Steyaert, Ron O. Dror, Brian K. Kobilka. Nature 2015, 524, 315-321.

(Publications 2 and 3 document the collaboration between P. Gmeiner and B. Kobilka, the results described are related but not identical to the BaCaTeC-funded project.)


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