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Structural determinants of dual incretin receptor agonism by tirzepatide
Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
National Academy of Sciences
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9060465/ https://www.ncbi.nlm.nih.gov/pubmed/35333651 http://dx.doi.org/10.1073/pnas.2116506119 |
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author | Sun, Bingfa Willard, Francis S. Feng, Dan Alsina-Fernandez, Jorge Chen, Qi Vieth, Michal Ho, Joseph D. Showalter, Aaron D. Stutsman, Cynthia Ding, Liyun Suter, Todd M. Dunbar, James D. Carpenter, John W. Mohammed, Faiz Ahmad Aihara, Eitaro Brown, Robert A. Bueno, Ana B. Emmerson, Paul J. Moyers, Julie S. Kobilka, Tong Sun Coghlan, Matthew P. Kobilka, Brian K. Sloop, Kyle W. |
author_facet | Sun, Bingfa Willard, Francis S. Feng, Dan Alsina-Fernandez, Jorge Chen, Qi Vieth, Michal Ho, Joseph D. Showalter, Aaron D. Stutsman, Cynthia Ding, Liyun Suter, Todd M. Dunbar, James D. Carpenter, John W. Mohammed, Faiz Ahmad Aihara, Eitaro Brown, Robert A. Bueno, Ana B. Emmerson, Paul J. Moyers, Julie S. Kobilka, Tong Sun Coghlan, Matthew P. Kobilka, Brian K. Sloop, Kyle W. |
author_sort | Sun, Bingfa |
collection | PubMed |
description | Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor (GLP-1R). In addition to GIPR signaling, the pathway bias at the GLP-1R may contribute to the efficacy of tirzepatide at improving glucose control and body weight regulation in type 2 diabetes mellitus. To investigate the structural basis for the differential signaling of tirzepatide, mechanistic pharmacology studies were allied with cryogenic electron microscopy. Here, we report high-resolution structures of tirzepatide in complex with the GIPR and GLP-1R. Similar to the native ligands, tirzepatide adopts an α-helical conformation with the N terminus reaching deep within the transmembrane core of both receptors. Analyses of the N-terminal tyrosine (Tyr1(Tzp)) of tirzepatide revealed a weak interaction with the GLP-1R. Molecular dynamics simulations indicated a greater propensity of intermittent hydrogen bonding between the lipid moiety of tirzepatide and the GIPR versus the GLP-1R, consistent with a more compact tirzepatide–GIPR complex. Informed by these analyses, tirzepatide was deconstructed, revealing a peptide structure–activity relationship that is influenced by acylation-dependent signal transduction. For the GIPR, Tyr1(Tzp) and other residues making strong interactions within the receptor core allow tirzepatide to tolerate fatty acid modification, yielding an affinity equaling that of GIP. Conversely, high-affinity binding with the extracellular domain of the GLP-1R, coupled with decreased stability from the Tyr1(Tzp) and the lipid moiety, foster biased signaling and reduced receptor desensitization. Together, these studies inform the structural determinants underlying the function of tirzepatide. |
format | Online Article Text |
id | pubmed-9060465 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | National Academy of Sciences |
record_format | MEDLINE/PubMed |
spelling | pubmed-90604652022-05-03 Structural determinants of dual incretin receptor agonism by tirzepatide Sun, Bingfa Willard, Francis S. Feng, Dan Alsina-Fernandez, Jorge Chen, Qi Vieth, Michal Ho, Joseph D. Showalter, Aaron D. Stutsman, Cynthia Ding, Liyun Suter, Todd M. Dunbar, James D. Carpenter, John W. Mohammed, Faiz Ahmad Aihara, Eitaro Brown, Robert A. Bueno, Ana B. Emmerson, Paul J. Moyers, Julie S. Kobilka, Tong Sun Coghlan, Matthew P. Kobilka, Brian K. Sloop, Kyle W. Proc Natl Acad Sci U S A Biological Sciences Tirzepatide (LY3298176) is a fatty-acid-modified, dual incretin receptor agonist that exhibits pharmacology similar to native GIP at the glucose-dependent insulinotropic polypeptide receptor (GIPR) but shows bias toward cyclic adenosine monophosphate signaling at the glucagon-like peptide-1 receptor (GLP-1R). In addition to GIPR signaling, the pathway bias at the GLP-1R may contribute to the efficacy of tirzepatide at improving glucose control and body weight regulation in type 2 diabetes mellitus. To investigate the structural basis for the differential signaling of tirzepatide, mechanistic pharmacology studies were allied with cryogenic electron microscopy. Here, we report high-resolution structures of tirzepatide in complex with the GIPR and GLP-1R. Similar to the native ligands, tirzepatide adopts an α-helical conformation with the N terminus reaching deep within the transmembrane core of both receptors. Analyses of the N-terminal tyrosine (Tyr1(Tzp)) of tirzepatide revealed a weak interaction with the GLP-1R. Molecular dynamics simulations indicated a greater propensity of intermittent hydrogen bonding between the lipid moiety of tirzepatide and the GIPR versus the GLP-1R, consistent with a more compact tirzepatide–GIPR complex. Informed by these analyses, tirzepatide was deconstructed, revealing a peptide structure–activity relationship that is influenced by acylation-dependent signal transduction. For the GIPR, Tyr1(Tzp) and other residues making strong interactions within the receptor core allow tirzepatide to tolerate fatty acid modification, yielding an affinity equaling that of GIP. Conversely, high-affinity binding with the extracellular domain of the GLP-1R, coupled with decreased stability from the Tyr1(Tzp) and the lipid moiety, foster biased signaling and reduced receptor desensitization. Together, these studies inform the structural determinants underlying the function of tirzepatide. National Academy of Sciences 2022-03-25 2022-03-29 /pmc/articles/PMC9060465/ /pubmed/35333651 http://dx.doi.org/10.1073/pnas.2116506119 Text en Copyright © 2022 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by/4.0/This open access article is distributed under Creative Commons Attribution License 4.0 (CC BY) (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Biological Sciences Sun, Bingfa Willard, Francis S. Feng, Dan Alsina-Fernandez, Jorge Chen, Qi Vieth, Michal Ho, Joseph D. Showalter, Aaron D. Stutsman, Cynthia Ding, Liyun Suter, Todd M. Dunbar, James D. Carpenter, John W. Mohammed, Faiz Ahmad Aihara, Eitaro Brown, Robert A. Bueno, Ana B. Emmerson, Paul J. Moyers, Julie S. Kobilka, Tong Sun Coghlan, Matthew P. Kobilka, Brian K. Sloop, Kyle W. Structural determinants of dual incretin receptor agonism by tirzepatide |
title | Structural determinants of dual incretin receptor agonism by tirzepatide |
title_full | Structural determinants of dual incretin receptor agonism by tirzepatide |
title_fullStr | Structural determinants of dual incretin receptor agonism by tirzepatide |
title_full_unstemmed | Structural determinants of dual incretin receptor agonism by tirzepatide |
title_short | Structural determinants of dual incretin receptor agonism by tirzepatide |
title_sort | structural determinants of dual incretin receptor agonism by tirzepatide |
topic | Biological Sciences |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9060465/ https://www.ncbi.nlm.nih.gov/pubmed/35333651 http://dx.doi.org/10.1073/pnas.2116506119 |
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