[19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors

Ballesteros, Juan A.; Weinstein, Harel

doi:10.1016/s1043-9471(05)80049-7

Cited by 2,838 publications

(2,602 citation statements)

References 104 publications

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“…As expected, relative maxima of these indices are found at positions widely recognized as wellconserved (and referred to as ".50" in the BallesterosWeinstein numbering scheme 51 ). It is interesting to note that the chosen anchoring point in helix 5, a proline at 5.50, is less conserved compared to the reference points of the other helices.…”

Section: Functional Conservation Profiles Of Tm Helices In Classsupporting

confidence: 72%

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Kratochwil

Malherbe

Lindemann

et al. 2005

J. Chem. Inf. Model.

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G protein-coupled receptors (GPCRs) share a common architecture consisting of seven transmembrane (TM) domains. Various lines of evidence suggest that this fold provides a generic binding pocket within the TM region for hosting agonists, antagonists, and allosteric modulators. Here, a comprehensive and automated method allowing fast analysis and comparison of these putative binding pockets across the entire GPCR family is presented. The method relies on a robust alignment algorithm based on conservation indices, focusing on pharmacophore-like relationships between amino acids. Analysis of conservation patterns across the GPCR family and alignment to the rhodopsin X-ray structure allows the extraction of the amino acids lining the TM binding pocket in a so-called ligand binding pocket vector (LPV). In a second step, LPVs are translated to simple 3D receptor pharmacophore models, where each amino acid is represented by a single spherical pharmacophore feature and all atomic detail is omitted. Applications of the method include the assessment of selectivity issues, support of mutagenesis studies, and the derivation of rules for focused screening to identify chemical starting points in early drug discovery projects. Because of the coarseness of this 3D receptor pharmacophore model, however, meaningful scoring and ranking procedures of large sets of molecules are not justified. The LPV analysis of the trace amine-associated receptor family and its experimental validation is discussed as an example. The value of the 3D receptor model is demonstrated for a class C GPCR family, the metabotropic glutamate receptors.

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Section: Functional Conservation Profiles Of Tm Helices In Classsupporting

confidence: 72%

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Kratochwil

Malherbe

Lindemann

et al. 2005

J. Chem. Inf. Model.

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“…In the extracellular half of the receptor, TM7 bends towards TM6 using as pivot point the kink at G395 7.50b (Wooten numbering in superscript 25 ) (Fig. 3a), equivalent to the conserved G 7.42 (Ballesteros-Weinstein numbering for family A GPCRs in superscript 35 ) in family A GPCRs 36 . In the inactive family B GPCR structures, the extracellular halves of TM6 and TM7, including ECL3, exhibit high crystallographic temperature factors indicating structural flexibility.…”

Section: Comparison With Inactive Family B Receptorsmentioning

confidence: 99%

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Zhang

Sun

Feng

et al. 2017

Nature

488

568

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Summary Glucagon-like peptide-1 (GLP-1) is a hormone with essential roles in regulating insulin secretion, carbohydrate metabolism and appetite. GLP-1 effects are mediated through binding to GLP-1R, a family B G protein-coupled receptor (GPCR) signaling primarily through the stimulatory G protein Gs. Family B GPCRs are important therapeutic targets, however our understanding of their mechanism of action is limited by the lack of structural information on activated and full-length receptors. Here we show the electron cryo-microscopy structure of the peptide-activated GLP-1R:Gs complex at near atomic resolution. The peptide is clasped between the N-terminal domain and transmembrane core of the receptor, further stabilized by extracellular loops. Conformational changes in the transmembrane domain result in a sharp kink in the middle of transmembrane helix 6, which pivots its intracellular half outward to accommodate the α5 helix of GαsRas. These results provide a structural framework for understanding family B receptor activation through hormone binding.

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“…2). The tetrazole ring of NNC0640 inserts into a cleft between helices VI and VII forming hydrogen bonds with S350 6.41b and N404 7.61b (numbers in superscript refer to the modified Ballesteros-Weinstein numbering system for class B GPCRs 14,15 ). The benzamide group of the ligand forms an additional polar interaction with S350 6.41b , while the urea carbonyl oxygen hydrogen bonds with T353 6.44b .…”

Section: Gcgr Binding Mode Of the Nam Nnc0640mentioning

confidence: 99%

Structure of the full-length glucagon class B G-protein-coupled receptor

Zhang

Qiao

Yang

et al. 2017

Nature

189

172

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The human glucagon receptor (GCGR) belongs to the class B G protein-coupled receptor (GPCR) family and plays a key role in glucose homeostasis and the pathophysiology of type 2 diabetes. Here we report the 3.0 Å crystal structure of full-length GCGR containing both extracellular domain (ECD) and transmembrane domain (TMD) in an inactive conformation. The two domains are connected by a 12-residue segment termed the ‘stalk’, which adopts a β-strand conformation, instead of forming an α-helix as observed in the previously solved structure of GCGR-TMD. The first extracellular loop (ECL1) exhibits a β-hairpin conformation and interacts with the stalk to form a compact β-sheet structure. Hydrogen/deuterium exchange, disulfide cross-linking and molecular dynamics studies suggest that the stalk and ECL1 play critical roles in modulating peptide ligand binding and receptor activation. These insights into the full-length GCGR structure deepen our understanding about the signaling mechanisms of class B GPCRs.

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[19] Integrated methods for the construction of three-dimensional models and computational probing of structure-function relations in G protein-coupled receptors

Cited by 2,838 publications

References 104 publications

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

An Automated System for the Analysis of G Protein-Coupled Receptor Transmembrane Binding Pockets: Alignment, Receptor-Based Pharmacophores, and Their Application

Cryo-EM structure of the activated GLP-1 receptor in complex with a G protein

Structure of the full-length glucagon class B G-protein-coupled receptor

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