|
Final report:
This report covers the establishment of a collaboration between our labs at the University of Würzburg and at Stanford University to investigate the mechanisms, how receptors are switched on and off.
As a background, it is important to know that receptors in general, and notably the family of G-protein-coupled receptors (GPCRs), are the targets of therapeutic drugs, and that therefore they belong to the most important molecules for medicine. There are almost 1,000 different types of GPCRs in the human body, which can very specifically bind natural ligands (hormones and neurotransmitters) and also synthetic drugs – such as beta-blockers, opiates, antihistamines etc. Studies on the structure and function of these receptors are therefore of extreme importance both for basic science and the pharmaceutical industry.
Our collaboration centered on two separate methodologies to analyze in detail the mechanisms of hormones and synthetic drugs can switch these receptors on and off. The Kobilka lab used structural analyses by X-ray crystallography on isolated, crystallized receptors (with and without additional proteins) in the active and the inactive states. The Lohse lab analyzed physiological settings by investigating with fluorescence microscopy in intact cells. Bringing these approaches together, and combining this with computer modelling, should give us a comprehensive view of the switching mechanisms in receptors.
Key publications:
Common publications
Kenakin T, Agnati LF, Caron M, Fredholm B, Guidoli D, Kobilka BK, Lefkowitz RJ, Lohse MJ, Woods A, Fuxe K (2010) International Workshop at the Nobel Forum, Karolinska Institutet on G protein-coupled receptors: finding the words to describe monomers, oligomers, and their molecular mechanisms and defining their meaning. Can a consensus be reached? J Recept Signal Transduct Res. 30, 284-286
Khelashvili G, Dorff K, Shan J, Camacho-Artacho M, Skrabanek L, Vroling B, Bouvier M, Devi LA, George SR, Javitch JA, Lohse MJ, Milligan G, Neubig RR, Palczewski K, Parmentier M, Pin JP, Vriend G, Campagne F, Filizola M (2010) GPCR-OKB: the G protein coupled receptor oligomer knowledge base. Bioinformatics 26, 1804-5
Separate key publications
Rosenbaum DM, Rasmussen SG, Kobilka BK (2009) The structure and function of G-protein-coupled receptors. Nature 459:356-63
Bokoch MP, Zou Y, Rasmussen SG, Liu CW, Nygaard R, Rosenbaum DM, Fung JJ, Choi HJ, Thian FS, Kobilka TS, Puglisi JD, Weis WI, Pardo L, Prosser RS, Mueller L, Kobilka BK. Ligand-specific regulation of the extracellular surface of a G-protein-coupled receptor. Nature 463, 108-12
Vilardaga JP, Nikolaev VO, Lorenz K, Ferrandon S, Zhuang Z, Lohse MJ (2008) Conformational cross-talk between ?2A-adrenergic and ?-opioid receptors controls cell signaling. Nature Chemical Biology 4, 126-131
Nikolaev VO, Moshkov A, Lyon AR, Miragoli M, Novak P, Paur H, Lohse MJ, Korchev YE, Harding SE, Gorelik J (2010) ?2-Adrenergic receptor redistribution in heart failure changes cAMP compartmentation. Science 327, 1653-1657
Hoffmann C, Gaietta G, Zürn A, Adams SR, Terillon S, Ellisman MH, Tsien RY, Lohse MJ (2010) Fluorescent labelling of tetracysteine-tagged proteins in intact cells. Nature Prot. 5, 1666-1677
Additional Comments 2023:
The common work has resulted in a deep understanding of the molecular mechanisms of receptors (GPCRs) and has also received considerable recognition.
Of particular note, the symposium in 2010 at the Karolinska Institute, to which a small group of receptor researchers were invited and which is summarized in the common publication Kenakin et al. 2010, was an important step in the selection of the Nobel prize for GPCRs. The Nobel prize was awarded in 2012 to two participants of the symposium, the co-applicant of this grant, Brian Kobilka, and our common mentor, Robert Lefkowitz.
Our common work was largely complemented and in many parts carried out by one of Brian Kobilka’s collaborators, Marta Filizola. This continuation was supported by a common 5-year grant (extended by another two years) to Marta Filizola and Martin Lohse from the US National Institutes of Health (1R01DA038882). It was also supported by an Advanced Grant of the European Research Council, ERC, to Martin Lohse (ERC-AdG-232944 TOPAS).
Publications
In addition to the publications mentioned above, the following publications have resulted from this collaboration:
Ferré S, Casadó V, Devi LA, Filizola M, Jockers R, Lohse MJ, Milligan G, Pin JP, Guitart X (2014) G protein-coupled receptor oligomerization revisited: functional and pharmacological perspectives. Pharmacol Rev. 66, 413-434
Meral D, Provasi D, Prada-Gracia D, Möller J, Marino K, Lohse MJ, Filizola M (2018) Molecular details of dimerization kinetics reveal negligible populations of transient µ-opioid receptor homodimers at physiological concentrations. Sci. Rep. 8:7705
Thibado JK, Tano JY, Lee J, Salas-Estrada L, Provasi D, Strauss A, Marcelo Lamim Ribeiro J, Xiang G, Broichhagen J, Filizola M, Lohse MJ, Levitz J (2021) Differences in interactions between transmembrane domains tune the activation of metabotropic glutamate receptors. Elife 10, e67027
|
