Structural insights into the activation of GLP-1R by a small molecule agonist

Ma, Honglei; Huang, Wei; Wang, Xiaoxi; Zhao, Lihua; Jiang, Yi; Liu, Feng; Guo, Wei; Sun, Xianqiang; Zhong, Wenge; Yuan, Daopeng; Xu, Heng

doi:10.1038/s41422-020-0384-8

Cited by 35 publications

(84 citation statements)

References 12 publications

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“…It shares a high degree of sequence similarity in the TMD region with GLP-1R (61%) that has been studied extensively both structurally and functionally. 31 Thus, inactive, intermediate and active GLP-1R structures published previously 13,17,[32][33][34][35] provide good references for the present study. Superimposing the TMD of GLP-2R with that of GLP-1R reveals that activated GLP-2R shows a similar conformation to that of GLP-1-bound or ExP5-bound GLP-1R-G s complexes 13,17 (Cα RMSD = 1.41 and 0.91 Å, respectively), distinct from inactive GLP-1R 33 (Cα RMSD = 1.79 Å).…”

Section: Conformational Changesmentioning

confidence: 73%

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A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

et al. 2020

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Glucagon-like peptides (GLP-1 and GLP-2) are two proglucagon-derived intestinal hormones that mediate distinct physiological functions through two related receptors (GLP-1R and GLP-2R) which are important drug targets for metabolic disorders and Crohn’s disease, respectively. Despite great progress in GLP-1R structure determination, our understanding on the differences of peptide binding and signal transduction between these two receptors remains elusive. Here we report the electron microscopy structure of the human GLP-2R in complex with GLP-2 and a Gs heterotrimer. To accommodate GLP-2 rather than GLP-1, GLP-2R fine-tunes the conformations of the extracellular parts of transmembrane helices (TMs) 1, 5, 7 and extracellular loop 1 (ECL1). In contrast to GLP-1, the N-terminal histidine of GLP-2 penetrates into the receptor core with a unique orientation. The middle region of GLP-2 engages with TM1 and TM7 more extensively than with ECL2, and the GLP-2 C-terminus closely attaches to ECL1, which is the most protruded among 9 class B G protein-coupled receptors (GPCRs). Functional studies revealed that the above three segments of GLP-2 are essential for GLP-2 recognition and receptor activation, especially the middle region. These results provide new insights into the molecular basis of ligand specificity in class B GPCRs and may facilitate the development of more specific therapeutics.

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Section: Conformational Changesmentioning

confidence: 73%

“…Comparison of active GLP-2R with inactive, agonist-bound and both agonist-bound and G protein-coupled active GLP-1R. 13,17,[32][33][34][35] Receptor ECD and G protein are omitted for clarity.…”

Section: Conformational Changesmentioning

confidence: 99%

A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

et al. 2020

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“…Different from the two-domain model for peptide binding, small-molecule ligands have greatly reduced contacts with the receptor. As shown in Figure 3C, five non-peptidic GLP-1R modulators were structurally observed either in the upper half of the orthosteric pocket (TT-OAD2, LY3502970, PF-06882961, and RGT1381) [24,25,38,39] or at the TM1-TM2 interface kinases, or lipases. Based on their structural relatedness, GPCRs are divided into five families: class A (rhodopsin), class B1 (secretin), class B2 (adhesion), class C (glutamate), and class F (frizzled/smoothened).…”

Section: Ligand Recognitionmentioning

confidence: 99%

Structural perspective of class B1 GPCR signaling

Cong

Liang

Zhou

et al. 2022

Trends in Pharmacological Sciences

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Class B1 G protein-coupled receptors (GPCRs) play important roles in human physiology and disease pathology. Using cryo-electron microscopy (cryo-EM) and X-ray crystallography, the 3D structures of all 15 members of this receptor subfamily have been determined in recent years at the near-atomic level. Although they share many structural commonalities, they show distinct features in terms of ligand recognition and receptor activation. In-depth structural analyses have yielded valuable insights into the N termini of both peptide hormones and cognate receptors, the outward movement of transmembrane helix 6 (TM6), the allosteric modulation sites located in the transmembrane domain (TMD), and the constitutive signaling bias mediated by receptor splice variants. These provide new directions for the design of better therapeutic agents, thereby making these targets more druggable. Rapid advancesG protein-coupled receptors (GPCRs, see Glossary) are the most abundant membrane proteins involved in numerous physiological functions [1]. One GPCR class, the B1 or secretin family, comprises 15 receptors for peptide hormones that regulate a variety of biological processes ranging from growth and development to metabolism and neuroactivities, thereby making them important therapeutic targets for many diseases [2]. Several drugs against this class have been successfully launched to the market, and glucagon-like peptide 1 (GLP-1) and parathyroid hormone (PTH) receptor agonists have reached 'blockbuster' status [3,4]. In earlier years X-ray crystallography and nuclear magnetic resonance (NMR) structural studies on class B1 GPCRs mainly focused on the apo state and ligand-receptor complex structures (Table S1 in the supplemental material online), providing substantial information about the conformations of these receptor extracellular domains (ECDs) and transmembrane domains (TMDs), as well as about the structural basis of ligand recognition. To deepen our knowledge on the structure-activity relationship of these ligand-receptor pairs, the first two full-length structures were determined using single-particle cryo-electron microscopy (cryo-EM) in 2017 [5,6]. Since then the cryo-EM structures for all 15 members of class B1 GPCRs have been solved (Figure 1), not only giving valuable information about hormone recognition and receptor activation from a class-wide perspective but also providing a useful template for the design and development of better peptidic and/or small-molecule drugs [7][8][9][10][11][12][13][14][15][16].

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“…However, suffering from low oral bioavailability due to metabolism by esterase in the gut as well as limitation of photosynthesis (15), this class of GLP-1R agonists is precluded from further development. Meanwhile, a handful of non-peptidic ligands with distinct pharmacological properties were identified in the past decades including TT-OAD2 (12), LY3502970 (27), CHU-128 (22), PF-06882961 (22) and RGT1383 (28). While a few have entered into clinical trials, none was regulatory approved for clinical use.…”

Section: Discussionmentioning

confidence: 99%

Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24

Cong¹,

Zhou²,

Li³

et al. 2022

Preprint

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Glucagon-like peptide-1 receptor (GLP-1R) agonists are effective in treating type 2 diabetes and obesity with proven cardiovascular benefits. However, most of them are peptides and require subcutaneous injection except for orally available semaglutide. Boc5 was identified as the first orthosteric non-peptidic agonist of GLP-1R that mimics a broad spectrum of bioactivities of GLP-1 in vitro and in vivo. Here, we report the cryo-electron microscopy structures of Boc5 and its analog WB4-24 in complex with the human GLP-1R and Gs protein. Bound to the extracellular domain, extracellular loop 2, and transmembrane (TM) helices 1, 2, 3 and 7, one arm of both compounds inserted deeply into the bottom of the orthosteric binding pocket that is usually accessible by peptidic agonists, thereby partially overlapping with the residues A8-D15 in GLP-1. The other three arms, meanwhile, extended to the TM1-TM7, TM1-TM2, and TM2-TM3 clefts showing an interaction feature substantially similar to a previously known small molecule agonist LY3502970. Such a unique binding mode creates a distinct conformation that confers both peptidomimetic agonism and biased signaling induced by non-peptidic modulators at GLP-1R. Further, the conformational difference between Boc5 and WB4-24, two closed related compounds, provides a structural framework for fine tuning of pharmacological efficacy in the development of future small molecule therapeutics targeting GLP-1R.

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Structural insights into the activation of GLP-1R by a small molecule agonist

Cited by 35 publications

References 12 publications

A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

A unique hormonal recognition feature of the human glucagon-like peptide-2 receptor

Structural perspective of class B1 GPCR signaling

Structural basis of peptidomimetic agonism revealed by small molecule GLP-1R agonists Boc5 and WB4-24

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