scholarly journals Analysis of Hyperekplexia Mutations Identifies Transmembrane Domain Rearrangements That Mediate Glycine Receptor Activation

2013 ◽  
Vol 288 (47) ◽  
pp. 33760-33771 ◽  
Author(s):  
Anna Bode ◽  
Joseph W. Lynch
Keyword(s):  
Transmembrane Domain ◽  
Glycine Receptor ◽  
Receptor Activation

scholarly journals Cryo-EM structure of the human histamine H1 receptor/Gq complex

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Ruixue Xia ◽  
Na Wang ◽  
Zhenmei Xu ◽  
Yang Lu ◽  
Jing Song ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Binding Pocket ◽  
Receptor Activation ◽  
Intracellular Loop ◽  
Cryo Electron Microscopy ◽  
Allergy Treatment ◽  
Domain 3 ◽  
Extracellular Side ◽  
Key Residues ◽  
Loop 2

AbstractHistamine receptors play important roles in various pathophysiological conditions and are effective targets for anti-allergy treatment, however the mechanism of receptor activation remain elusive. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human H1R in complex with a Gq protein in an active conformation via a NanoBiT tethering strategy. The structure reveals that histamine activates receptor via interacting with the key residues of both transmembrane domain 3 (TM3) and TM6 to squash the binding pocket on the extracellular side and to open the cavity on the intracellular side for Gq engagement in a model of “squash to activate and expand to deactivate”. The structure also reveals features for Gq coupling, including the interaction between intracellular loop 2 (ICL2) and the αN-β junction of Gq/11 protein. The detailed analysis of our structure will provide a framework for understanding G-protein coupling selectivity and clues for designing novel antihistamines.

scholarly journals Residues within the Transmembrane Domain of the Glucagon-Like Peptide-1 Receptor Involved in Ligand Binding and Receptor Activation: Modelling the Ligand-Bound Receptor

2011 ◽  
Vol 25 (10) ◽  
pp. 1804-1818 ◽  
Author(s):  
K. Coopman ◽  
R. Wallis ◽  
G. Robb ◽  
A. J. H. Brown ◽  
G. F. Wilkinson ◽  
...  
Keyword(s):  
Ligand Binding ◽  
Structural Model ◽  
Transmembrane Domain ◽  
Transmembrane Helix ◽  
Receptor Activation ◽  
Agonist Affinity ◽  
Camp Generation ◽  
N Terminus ◽  
Glucagon Like Peptide ◽  
Glucagon Like Peptide 1

The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.

scholarly journals Actions of the Small Molecule Ligands SW106 and AH-3960 on the Type-1 Parathyroid Hormone Receptor

2015 ◽  
Vol 29 (2) ◽  
pp. 307-321 ◽  
Author(s):  
Percy H. Carter ◽  
Thomas Dean ◽  
Brijesh Bhayana ◽  
Ashok Khatri ◽  
Raj Rajur ◽  
...  
Keyword(s):  
Parathyroid Hormone ◽  
Small Molecule ◽  
Hormone Receptor ◽  
Transmembrane Domain ◽  
Receptor Activation ◽  
Blood Calcium ◽  
Parathyroid Hormone Receptor ◽  
Peptide Analog ◽  
Amino Terminal ◽  
Small Molecule Ligands

Abstract The parathyroid hormone receptor-1 (PTHR1) plays critical roles in regulating blood calcium levels and bone metabolism and is thus of interest for small-molecule ligand development. Of the few small-molecule ligands reported for the PTHR1, most are of low affinity, and none has a well-defined mechanism of action. Here, we show that SW106 and AH-3960, compounds previously identified to act as an antagonist and agonist, respectively, on the PTHR1, each bind to PTHR1-delNT, a PTHR1 construct that lacks the large amino-terminal extracellular domain used for binding endogenous PTH peptide ligands, with the same micromolar affinity with which it binds to the intact PTHR1. SW106 antagonized PTHR1-mediated cAMP signaling induced by the peptide analog, M-PTH(1–11), as well as by the native PTH(1–9) sequence, as tethered to the extracellular end of transmembrane domain (TMD) helix-1 of the receptor. SW106, however, did not function as an inverse agonist on either PTHR1-H223R or PTHR1-T410P, which have activating mutations at the cytoplasmic ends of TMD helices 2 and 6, respectively. The overall data indicate that SW106 and AH-3960 each bind to the PTHR1 TMD region and likely to within an extracellularly exposed area that is occupied by the N-terminal residues of PTH peptides. Additionally, they suggest that the inhibitory effects of SW106 are limited to the extracellular portions of the TMD region that mediate interactions with agonist ligands but do not extend to receptor-activation determinants situated more deeply in the helical bundle. The study helps to elucidate potential mechanisms of small-molecule binding at the PTHR1.

scholarly journals Two transmembrane dimers of the bovine papillomavirus E5 oncoprotein clamp the PDGF β receptor in an active dimeric conformation

2017 ◽  
Vol 114 (35) ◽  
pp. E7262-E7271 ◽  
Author(s):  
Alexander G. Karabadzhak ◽  
Lisa M. Petti ◽  
Francisco N. Barrera ◽  
Anne P. B. Edwards ◽  
Andrés Moya-Rodríguez ◽  
...  
Keyword(s):  
Transmembrane Domain ◽  
Transmembrane Protein ◽  
Receptor Activation ◽  
Bovine Papillomavirus ◽  
Detailed Model ◽  
E5 Protein ◽  
Membrane Modeling ◽  
E5 Oncoprotein ◽  
Β Receptor ◽  
Dynamics Simulations

The dimeric 44-residue E5 protein of bovine papillomavirus is the smallest known naturally occurring oncoprotein. This transmembrane protein binds to the transmembrane domain (TMD) of the platelet-derived growth factor β receptor (PDGFβR), causing dimerization and activation of the receptor. Here, we use Rosetta membrane modeling and all-atom molecular dynamics simulations in a membrane environment to develop a chemically detailed model of the E5 protein/PDGFβR complex. In this model, an active dimer of the PDGFβR TMD is sandwiched between two dimers of the E5 protein. Biochemical experiments showed that the major PDGFβR TMD complex in mouse cells contains two E5 dimers and that binding the PDGFβR TMD to the E5 protein is necessary and sufficient to recruit both E5 dimers into the complex. These results demonstrate how E5 binding induces receptor dimerization and define a molecular mechanism of receptor activation based on specific interactions between TMDs.

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