Molecular principles of patho-physiological mechanisms of the incretin receptors with general implications for family B GPCRs
Final Report Abstract
The incretin receptor GIPR and GLP-1R and the GlucR play crucial roles in glucose homeostasis. Targeting these receptors is a promising option in diabetes and obesity treatment. This project aimed on a comprehensive investigation of structural prerequisites of these class B GPCRs, the design of new compounds targeting these receptors and their testing in rodent models of obesity and disturbed glucose homeostasis as well as the elucidation of molecular insights into the function of newly designed compounds. Family B GPCRs share a high structural homology to family A GPCRs. Decisive differences include their activation by peptides bound to large extracellular domains and a different signature of preserved amino acids involved in signal transfer. To understand the specific role of peptides in receptor activation the complete binding mechanism has to be elucidated. Simulation of peptide mimicking peptides to receptors in the Hildebrand laboratory indicate a complex mechanism of recognition and binding involving all flexible extracellular parts of the receptor. A fragment based approach was developed to automatically model the conformational space of these flexible parts and integrated into a web service that promotes modeling and visualization of GPCRs. Further efforts are required to elucidate the binding mechanism of peptides and allostery of receptors. In the Tschöp part of this project a variety of compounds were designed which follow a completely new strategy: i) design of unimolecular multi-agonists engineered to simultaneously activate multiple key metabolic signaling pathways; ii) the design and preclinical evaluation of drugs engineered to deliver nuclear hormones specifically into cells expressing specific incretin hormone receptors; i.e. delivery of estrogen via GLP-1 as peptide carrier, delivery of T3 via glucagon as the peptide carrier and delivery of dexamethasone using GLP-1 as the peptide carrier. Collectively, our data demonstrate that GLP-1 based sequence hybrids with GIP or GIP/Glucagon carries a high potential to pharmacologically improve body weight and deranged glycemic control. Our chimeras between peptide hormones and nuclear hormones further demonstrate that peptide hormone selective nuclear hormone transport can be used to improve glucose and lipid metabolism without detrimental off-target effects in tissues devoid of the peptide hormone receptor. In Biebermann part of this project the elucidation of pathways induced by dual and triple agonists in addition to activation of Gs/adenylyl cyclase activation which is the main signaling pathways of class B GPCRs was performed. This pathway is seen as the major contributor to the incretin effect, however, in our part of the project we could demonstrate the multi-agonist that activate all three receptors, is capable to activate phospholipase C signaling in contrast to monoagonists and has an enhanced efficacy in action of TRPs. We conclude that this extended signaling profile of multi-agonist ligands is responsible for the superior effect on glucose homeostasis. By elucidation of the pathophysiological relevance of GIPR for glucose homeostasis we could demonstrate that variants in GIPR are unlikely to represent a frequent cause of disturbed glucose homeostasis. In sum, in this project new bioinformatics tools and compounds were designed and tested and molecular mechanisms were elucidated that are suitable for future application in patients to treat metabolic disorders.
Publications
- Targeted estrogen delivery reverses the metabolic syndrome. Nat Med. 2012;18:1847-56
Finan B, Yang B, Ottaway N, Stemmer K, Müller TD, Yi CX, Habegger K, Schriever SC, García- Cáceres C, Kabra DG, Hembree J, Holland J, Raver C, Seeley RJ, Hans W, Irmler M, Beckers J, de Angelis MH, Tiano JP, Mauvais-Jarvis F, Perez-Tilve D, Pfluger P, Zhang L, Gelfanov V, Dimarchi RD, Tschöp MH
(See online at https://doi.org/10.1038/nm.3009) - Unimolecular dual incretins maximize metabolic benefits in rodents, monkeys, and humans. Sci Transl Med. 2013;5:209ra151
Finan B, Ma T, Ottaway N, Müller TD, Habegger KM, Heppner KM, Kirchner H, Holland J, Hembree J, Raver C, Lockie SH, Smiley DL, Gelfanov V, Yang B, Hofmann S, Bruemmer D, Drucker DJ, Pfluger PT, Perez-Tilve D, Gidda J, Vignati L, Zhang L, Hauptman JB, Lau M, Brecheisen M, Uhles S, Riboulet W, Hainaut E, Sebokova E, Conde-Knape K, Konkar A, Dimarchi RD, Tschöp MH
(See online at https://doi.org/10.1126/scitranslmed.3007218) - Crystal structure of a common GPCR-binding interface for G protein and arrestin. Nat Commun. 2014 Sep 10;5:4801
Szczepek M, Beyrière F, Hofmann KP, Elgeti M, Kazmin R, Rose A, Bartl FJ, von Stetten D, Heck M, Sommer ME, Hildebrand PW, Scheerer P
(See online at https://doi.org/10.1038/ncomms5801) - GLP-1/glucagon co-agonism restores leptin responsiveness in obese mice chronically maintained on an obesogenic diet. Diabetes. 2014;63:1422-7
Clemmensen C, Chabenne J, Finan B, Sullivan L, Fischer K, Küchler D, Sehrer L, Ograjsek T, Hofmann S, Schriever SS, Pfluger PT, Pinkstaff J, Tschöp MH, Dimarchi R, Müller TD
(See online at https://doi.org/10.2337/db13-1609) - Position of transmembrane helix 6 determines receptor G protein coupling specificity. J Am Chem Soc. 2014 Aug 13;136(32):11244-7
Rose AS, Elgeti M, Zachariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW
(See online at https://doi.org/10.1021/ja5055109) - A rationally designed monomeric peptide triagonist corrects obesity and diabetes in rodents. Nat Med. 2015;21:27-36
Finan B, Yang B, Ottaway N, Smiley DL, Ma T, Clemmensen C, Chabenne J, Zhang L, Habegger KM, Fischer K, Campbell JE, Sandoval D, Seeley RJ, Bleicher K, Uhles S, Riboulet W, Funk J, Hertel C, Belli S, Sebokova E, Conde-Knape K, Konkar A, Drucker DJ, Gelfanov V, Pfluger PT, Müller TD, Perez-Tilve D, DiMarchi RD, Tschöp MH
(See online at https://doi.org/10.1038/nm.3761) - NGL Viewer: a web application for molecular visualization. Nucleic Acids Res. 2015 Jul 1;43(W1):W576-9
Rose AS, Hildebrand PW
(See online at https://doi.org/10.1093/nar/gkv402) - Role of Structural Dynamics at the Receptor G Protein Interface for Signal Transduction. PLoS One. 2015 Nov 25;10(11)
Rose AS, Zachariae U, Grubmüller H, Hofmann KP, Scheerer P, Hildebrand PW
(See online at https://doi.org/10.1371/journal.pone.0143399) - Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell. 2016 Oct 20;167(3):843-857
Finan B, Clemmensen C, Zhu Z, Stemmer K, Gauthier K, Müller L, De Angelis M, Moreth K, Neff F, Perez-Tilve D, Fischer K, Lutter D, Sánchez-Garrido MA, Liu P, Tuckermann J, Malehmir M, Healy ME, Weber A, Heikenwalder M, Jastroch M, Kleinert M, Jall S, Brandt S, Flamant F, Schramm KW, Biebermann H, Döring Y, Weber C, Habegger KM, Keuper M, Gelfanov V, Liu F, Köhrle J, Rozman J, Fuchs H, Gailus-Durner V, Hrabě de Angelis M, Hofmann SM, Yang B, Tschöp MH, DiMarchi R, Müller TD
(See online at https://doi.org/10.1016/j.cell.2016.09.014) - SL2: an interactive webtool for modeling of missing segments in proteins. Nucleic Acids Res. 2016 Jul 8;44(W1):W390-4
Ismer J, Rose AS, Tiemann JK, Goede A, Preissner R, Hildebrand PW
(See online at https://doi.org/10.1093/nar/gkw297) - GPCR-SSFE 2.0-a fragment-based molecular modeling web tool for Class A G-protein coupled receptors. Nucleic Acids Res. 2017 Jul 3;45(W1):W408-W415
Worth CL, Kreuchwig F, Tiemann JKS, Kreuchwig A, Ritschel M, Kleinau G, Hildebrand PW, Krause G
(See online at https://doi.org/10.1093/nar/gkx399) - Molecular Integration of Incretin and Glucocorticoid Action Reverses Immunometabolic Dysfunction and Obesity. Cell Metab. 2017;26:620-632.e6
Quarta C, Clemmensen C, Zhu Z, Yang B, Joseph SS, Lutter D, Yi CX, Graf E, García-Cáceres C, Legutko B, Fischer K, Brommage R, Zizzari P, Franklin BS, Krueger M, Koch M, Vettorazzi S, Li P, Hofmann SM, Bakhti M, Bastidas-Ponce A, Lickert H, Strom TM, Gailus-Durner V, Bechmann I, Perez- Tilve D, Tuckermann J, Hrabě de Angelis M, Sandoval D, Cota D, Latz E, Seeley RJ, Müller TD, DiMarchi RD, Finan B, Tschöp MH
(See online at https://doi.org/10.1016/j.cmet.2017.08.023) - Monomeric GLP-1/GIP/glucagon triagonism equally corrects obesity and dylipidemia in male and female mice. Mol Metab. 2017;6:440-446
Jall S, Sachs S, Clemmensen C, Finan B, Neff F, DiMarchi R, Tschöp MH, Müller TD, Hofmann SM
(See online at https://doi.org/10.1016/j.molmet.2017.02.002) - The New Biology and Pharmacology of Glucagon. Physiol Rev. 2017;97:721-766
Müller TD, Finan B, Clemmensen C, DiMarchi RD, Tschöp MH
(See online at https://doi.org/10.1152/physrev.00025.2016) - The Sustained Effects of a Dual GIP/GLP-1 Receptor Agonist, NNC0090-2746, in Patients with Type 2 Diabetes.Cell Metab. 2017 Aug 1;26(2):343-352.e2
Frias JP, Bastyr EJ 3rd, Vignati L, Tschöp MH, Schmitt C, Owen K, Christensen RH, DiMarchi RD
(See online at https://doi.org/10.1016/j.cmet.2017.07.011) - Treatment of Diabetes and Obesity by Rationally Designed Peptide Agonists Functioning at Multiple Metabolic Receptors. Endocr Dev. 2017;32:165-182
Khajavi N, Biebermann H, Tschöp M, DiMarchi R
(See online at https://doi.org/10.1159/000475737) - An incretin-based tri-agonist promotes superior insulin secretion from murine pancreatic islets via PLC activation.Cell Signal. 2018 Jul 25;51:13-22
Khajavi N, Finan B, Kluth O, Müller TD, Mergler S, Schulz A, Kleinau G, Scheerer P, Schürmann A, Gudermann T, Tschöp MH, Krude H, DiMarchi RD, Biebermann H
(See online at https://doi.org/10.1016/j.cellsig.2018.07.006) - Binding, Thermodynamics, and Selectivity of a Non-peptide Antagonist to the Melanocortin-4 Receptor. Front Pharmacol. 2018 Jun 1;9:560
Saleh N, Kleinau G, Heyder N, Clark T, Hildebrand PW, Scheerer P
(See online at https://doi.org/10.3389/fphar.2018.00560)
