Ligand Binding Pocket Formed by Evolutionarily Conserved Residues in the Glucagon-like Peptide-1 (GLP-1) Receptor Core Domain

Graaf

Journal of Biological Chemistry

et al. 2016

The glucagon-like peptide 1 receptor (GLP-1R) 6 and the glucagon receptor (GCGR) are class B G protein-coupled receptors (GPCRs) involved in insulin release and glucose homeostasis, respectively. Accordingly, they have attracted extensive attention for their importance as targets for therapeutic intervention of type 2 diabetes (1, 2). Class B GPCRs consist of an N-terminal extracellular domain (ECD) linked to a seven-transmembrane helical (7TM) region. Studies examining truncated, chimeric, and mutated ligand and receptor variants together with multiple ligand-bound ECD crystal structures and two class B 7TM domain crystal structures are consistent with a "two-domain" binding mechanism for peptide hormone ligands to the secretin-like class B GPCRs (3-5). According to this peptide ligand binding mechanism, the C terminus of the peptide hormone forms an initial complex with the ECD, allowing the N terminus of the ligand to interact with the 7TM domain. It is the N-terminal interactions that ultimately result in activation of the receptor and stimulation of downstream coupling to G proteins and other effectors that mediate intra-*

Section: Tm-binding Site Whereas In Glucagon-bound Gcgr the Ionic Isupporting

confidence: 68%

Structural Determinants of Binding the Seven-transmembrane Domain of the Glucagon-like Peptide-1 Receptor (GLP-1R)

Graaf

Journal of Biological Chemistry

et al. 2016

“…With the aim of modelling the glucagon-like peptide-1 (GLP1) 70 bound to the GLP1 receptor (GLP1R), homology models were built by utilizing the crystal structures of the CRF 1 R, the glucagon receptor (GCGR), and the ligand-bound ECD of GLP1R and the gastric inhibitory polypeptide receptor (GIPR) as templates 280 . The Authors found that the residues Asp 9 and Gly 4 75 in GLP-1 interacted with the conserved residues in EL 3 , while the binding site of GLP1R is constituted by conserved amino acids in the core domain.…”

Section: The Latest Milestone: Modelling Gpcr Classes B and Cmentioning

confidence: 99%

Expanding the horizons of G protein-coupled receptor structure-based ligand discovery and optimization using homology models

Cavasotto

Palomba

2015

Chem. Commun.

With >800 members in humans, the G protein-coupled receptor (GPCR) super-family is the target for more than 30% of the marketed drugs. The recent boom in GPCR crystallography has enabled the solution of ∼30 different GPCR structures, which boosted the identification and optimization of novel modulators and new chemical entities through structure-based strategies. However, the number of available structures represents a small part of the human GPCR druggable target space, and its complete coverage in the near future seems unlikely. Homology modelling represents a reliable tool to fill this gap, and hence to vastly expand the horizons of structure-based drug discovery and design. In this Feature Article, we show from a wealth of retrospective and prospective studies that in spite of the pitfalls of and standing challenges in homology modelling, structural models have been critical for the blossoming and success of GPCR structure-based lead discovery and optimization endeavours; in addition, they have also been instrumental in characterizing receptor-ligand interaction, guiding the design of site-directed mutagenesis and SAR studies, and assessing off-target effects. Considering though their current limitations, we also discuss the most pressing issues to develop more accurate homology modelling strategies, with a special focus on the integration of computational tools with biochemical, biophysical and QSAR data, highlighting methodological aspects and recent progress. The teachings of the three GPCR Dock community-wide assessments and the fresh developments in GPCR classes B, C and F are commented. This is a fast growing and highly promising field of research, and in the coming years, the use of high-quality models should enable the discovery of a growing number of potent, selective and efficient GPCR drug leads with high therapeutic potential through receptor structure-based strategies.

“…These templates were linked by a global alignment, which was used by Modeler to generate a full GLP-1R model with GLP-1(7-36)NH 2 bound. Modeler used 4 p-benzoylphenylalanine (Bpa) photoaffinity crosslinking-derived distance constraints between GLP-1 and GLP-1R (Chen et al, 2009(Chen et al, , 2010Miller et al, 2011) and two sets of constraints derived from reciprocal mutagenesis experiments that resulted in gain of function Vertongen et al, 2001;Moon et al, 2015), as shown in Table 1; the effect of these constraints was to provide additional information on the peptide-receptor interaction in the region between the TM and ECD templates. These reciprocal mutagenesis results were essentially the only mutagenesis results used in the generation of the model.…”

Section: Methodsmentioning

confidence: 99%

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures

et al. 2015

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. 240 and Q7.49 394 had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.