Project C01 – Evolution of functional selectivity in GPCR signal transduction

G protein-coupled receptors (GPCRs) transduce a high variety of different signals into the cell through specific binding of downstream signaling proteins such as Gs, Gi, Gq, G12/13 or arrestin. However, the structural and evolutionary basis for this signaling specificity is still not well understood. Here we propose a comprehensive computational analysis of receptor coupling specificity. For that purpose, we will combine phylogenetic analysis of receptors and interacting intracellular proteins with structural bioinformatics and latest generation molecular dynamics (MD) simulations. Our computational analysis aims to elucidate how common structural features underlying the specific signaling profiles have developed.


Prof. Dr. Peter Stadler (Project Leader)

Leipzig University, Faculty of Mathematics and Computer Science
Institute of Computer Science
Härtelstraße 16 – 18, D-04107 Leipzig

Phone +49 341 97 16690


Computational analysis of receptor coupling specificity by

  • phylogenetic analysis 
  • structural bioinformatics and latest generation molecular dynamics (MD) simulations


Mayol E, García-Recio A, Tiemann JKS, Hildebrand PW, Guixà-González R, Olivella M, Cordomí A. HomolWat: a web server tool to incorporate ‘homologous’ water molecules into GPCR structures. Nucleic Acids Res. 2020 Jul 2;48(W1):W54-W59. doi: 10.1093/nar/gkaa440. PMID: 32484557; PMCID: PMC7319549.

Rodríguez-Espigares I, Torrens-Fontanals M, Tiemann JKS, Aranda-García D, Ramírez-Anguita JM, Stepniewski TM, Worp N, Varela-Rial A, Morales-Pastor A, Medel-Lacruz B, Pándy-Szekeres G, Mayol E, Giorgino T, Carlsson J, Deupi X, Filipek S, Filizola M, Gómez-Tamayo JC, Gonzalez A, Gutiérrez-de-Terán H, Jiménez-Rosés M, Jespers W, Kapla J, Khelashvili G, Kolb P, Latek D, Marti-Solano M, Matricon P, Matsoukas MT, Miszta P, Olivella M, Perez-Benito L, Provasi D, Ríos S, R Torrecillas I, Sallander J, Sztyler A, Vasile S, Weinstein H, Zachariae U, Hildebrand PW, De Fabritiis G, Sanz F, Gloriam DE, Cordomi A, Guixà-González R, Selent J. GPCRmd uncovers the dynamics of the 3D-GPCRome. Nat Methods. 2020 Jul 13. doi: 10.1038/s41592-020-0884-y. Epub ahead of print. Erratum in: Nat Methods. 2020 Jul 23;: PMID: 32661425.

Indrischek H, Wieseke N, Stadler PF, Prohaska SJ. The Paralog-to-Contig AssignmentProblem: High quality gene models from fragmented assemblies. Alg Mol Biol. 2016; 11:1.

Lechner M, Findeiss S, Steiner L, Marz M, Stadler PF, Prohaska SJ. Proteinortho: Detection of (Co-)Orthologs in Large-Scale Analysis. BMC Bioinformatics. 2011; 12:124.

Hellmuth Marc, Wieseke N, Lechner M, Lenhof H-P, Middendorf M, Stadler PF. Phylogenetics from Paralogs. Proc Natl Acad Sci USA. 2015; 112:2058-63.

Indrischek H, Prohaska SJ, Gurevich V, Gurevich E, Stadler PF. Uncovering missing pieces: Duplication and deletion history of arrestins in Deuterostomes. BMC Evol Biol. 2017; 17:163.

Lokits AD, Indrischek H, Meiler J, Hamm HE, Stadler PF. Tracing the evolution of the heterotrimeric G protein subunit in Metazoa. BMC Evolutionary Biology. 2018; 18:51.

Rose AS, Zachariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW. Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction. PLoS One. 2015; 10:e0143399.

Rose AS, Elgeti M, Zachariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW. Position of Transmembrane Helix 6 Determines Receptor G Protein Coupling Specificity. J Am Chem Soc. 2014; 136:11244-7.

Tiemann JKS, Guixà-González R, Hildebrand PW, Rose AS. MDsrv: viewing and sharing molecular dynamics simulations on the web. Nat Methods. 2017; 14:1123-4.

Saleh N, Hucke O, Kramer G, Schmidt E, Montel F, Lipinski R, Ferger B, Clark T, Hildebrand PW, Tautermann CS. Multiple Binding Sites Contribute to the Mechanism of Mixed Agonistic and Positive Allosteric Modulators of the Cannabinoid CB1 Receptor. Angew Chem Int Ed Engl. 2018; 57:2580-5.

Scheerer P, Park JH, Hildebrand PW, Kim YJ, Krauss N, Choe HW, Hofmann KP, Ernst OP. Crystal structure of opsin in its G-protein-interacting conformation. 2008; 455:497-502.