Project C01 – Specificity and dynamics in signaling of peptide activated GPCRs
G protein-coupled receptors (GPCRs) transduce a wide variety of different signals into the cell through the specific binding of downstream signaling proteins such as Gs, Gi, or arrestin. However, the structural basis for this signaling specificity is not well understood. Here we investigate the specificity of coupling of selected peptide receptors to Gs or Gi proteins using molecular dynamics (MD) simulations. We analyze the dynamics of peptide ligand binding to the extracellular side and determine how the signal is mechanistically transmitted to the intracellular G-protein/arrestin binding pocket.
Evolution of functional specificity in GPCR signal transduction
Profject Leaders: Prof. Dr. Peter Stadler and Prof. Dr. Peter Hildebrand
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.
Contact
Prof. Dr. Peter Hildebrand (Project Leader)
Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, D-04107 Leipzig
Phone +49 341 97 15712
E-Mail
Web uni-leipzig.de/prof-dr-peter-w-hildebrand/
Franziska Reinhardt (PhD Student)
Leipzig University, Faculty of Mathematics and Computer Science
Institute of Computer Science
Härtelstraße 16 – 18, D-04107 Leipzig
Maik Pankonin (PhD-Student)
Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, D-04107 Leipzig
Florian Seufert (PhD-Student)
Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, D-04107 Leipzig
Passainte Ibrahim (Postdoc)
Leipzig University, Faculty of Medicine
Institute of Medical Physics and Biophysics
Härtelstraße 16 – 18, D-04107 Leipzig
Resources
- Computational analysis of receptor coupling specificity by structural bioinformatics and latest generation molecular dynamics (MD) simulations.
Publications
Batebi H, Pérez-Hernández G, Rahman SN, Lan B, Kamprad K, Shi M, Speck D, Tiemann JKS, Guixà-González R, Reinhardt F, Stadler PF, Papasergi-Scott MM, Skiniotis G, Scheerer P, Kobilka BK, Mathiesen JM, Liu X, Hildebrand PW. Mechanistic insights into G-protein coupling with an agonist-bound G-protein-coupled receptor. Nature Struct Mol Biol (2024). https://doi.org/10.1038/s41594-024-01334-2 .
Papasergi-Scott MM, Pérez-Hernández G, Batebi H, Gao Y, Eskici G, Seven AB, Panova O, Hilger D, Casiraghi M, He F, Maul L, Gmeiner P, Kobilka BK, Hildebrand PW, Skiniotis G. Time-resolved cryo-EM of G-protein activation by a GPCR. Nature. 2024. doi: 10.1038/s41586-024-07153-1.
Philipp M, Moth CW, Ristic N, Tiemann JKS, Seufert F, Panfilova A, Meiler J, Hildebrand PW, Stein A, Wiegreffe D, Staritzbichler R. MutationExplorer- a webserver for mutation of proteins and 3D visualization of energetic impacts. bioRxiv [Preprint]. 2024 Feb 28:2023.03.23.533926. doi: 10.1101/2023.03.23.533926 .
Reinhardt F, Kaiser A, Prömel S, Stadler PF. Evolution of Neuropeptide Y/RFamide-like receptors in Nematodes. Heliyon. 2024; 10:14 e34473. doi.org/10.1016/j.heliyon.2024.e34473.
Vieira Contreras F, Auger GM, Müller L, Richter V, Huetteroth W, Seufert F, Hildebrand PW, Scholz N, Thum AS, Ljaschenko D, Blanco-Redondo B, Langenhan T. The adhesion G-protein-coupled receptor mayo/CG11318 controls midgut development in Drosophila. Cell Rep. 2024 Jan 4;43(1):113640. doi: 10.1016/j.celrep.2023.113640.
Staritzbichler R, Ristic N, Stapke T, Hildebrand P. SmoothT – a server constructing low energy pathways from conformational ensembles for interactive visualization and enhanced sampling. Bioinformatics. 2023; 39:btad176.
Sala D, Batebi H, Ledwitch K, Hildebrand PW, Meiler J. Targeting in silico GPCR conformations with ultra-large library screening for hit discovery. Trends Pharmacol Sci. 2023; 44:150-61.
Sala D, Hildebrand PW, Meiler J. Biasing AlphaFold2 to predict GPCRs and Kinases with user-defined functional or structural properties. Front Mol Biosci. 2023; 10:1121962.
Canzler S, Fischer M, Ulbricht D, Ristic N, Hildebrand PW, Staritzbichler R. ProteinPrompt: a webserver for predicting protein–protein interactions. Bioinformatics Advances, Volume 2, Issue 1, 2022, vbac059, https://doi.org/10.1093/bioadv/vbac059.
Reinhard F, Stadler PF. ExceS-A: An Exon-Centric Split Aligner. JIB. 2022; pp. 20210040.
Schaller D, Lafond M, Stadler PF, Wieseke N, Hellmuth M. Indirect identification of horizontal gene transfer. Journal of Mathematical Biology volume 83, Article number: 10 (2021).https://doi.org/10.1007/s00285-021-01631-0.
Smith AA, Vogel A, Engberg O, Hildebrand PW, Huster D. A method to construct the dynamic landscape of a bio-membrane with experiment and simulation. Nat Commun. 2022; 13:108.
Stadler PF, Will S. Bi-alignments with affine gaps costs. Algorithms Mol Biol. 2022 May 16;17(1):10. doi: 10.1186/s13015-022-00219-7.PMID: 35578255.
Yang Y, Stensitzki T, Sauthof L, Schmidt A, Piwowarski P, Velazquez Escobar F, Michael N, Nguyen AD, Szczepek M, Brünig FN, Netz RR, Mroginski MA, Adam S, Bartl F, Schapiro I, Hildebrandt P, Scheerer P, Heyne K. Ultrafast proton-coupled isomerization in the phototransformation of phytochrome. Nat Chem. 2022 May 16. doi: 10.1038/s41557-022-00944-x. Online ahead of print. PMID: 35577919.
Heyder NA, Kleinau G, Speck D, Schmidt A, Paisdzior S, Szczepek M, Bauer B, Koch A, Gallandi M, Kwiatkowski D, Bürger J, Mielke T, Beck-Sickinger AG, Hildebrand PW, Spahn CMT, Hilger D, Schacherl M, Biebermann H, Hilal T, Kühnen P, Kobilka BK, Scheerer P. Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide. Cell Res. 2021; 31:1176-1189.
Reinhardt F, Stadler PF. ExceS-A: An Exon-Centric Split Aligner. J Integrative Bioinformatics. 2021; 19:40.
Schaller D, Lafond M, Stadler PF, Wiesecke N, Hellmuth M. Indirect identification of horizontal gene transfer. J. Math. Biol. 2021; 83:10.
Stadler PF. Aligments of Biomolecular Contact Maps. Interface Focus. 2021; 11: 66.
Ma X, Hu Y, Batebi H, Heng J, Xu J, Liu X, Niu X, Li H, Hildebrand PW, Jin C, Kobilka BK. Analysis of β2AR-Gs and β2AR-Gi complex formation by NMR spectroscopy. Proc Natl Acad Sci U S A. 2020; 117:23096-23105.
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.
Liu X, Xu X, Hilger D, Aschauer P, Tiemann JKS, Du Y, Liu H, Hirata K, Sun X, Guixà-González R, Mathiesen JM, Hildebrand PW, Kobilka BK. Structural Insights into the Process of GPCR-G Protein Complex Formation. Cell. 2019; 177:1243-1251.
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.
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.
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.
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.
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.
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.
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.
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.
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.
