Structure of the Human Angiotensin II Type 1 (AT1) Receptor Bound to Angiotensin II from Multiple Chemoselective Photoprobe Contacts Reveals a Unique Peptide Binding Mode

Abstract

Background: G protein-coupled receptors (GPCRs) modulate a plethora of physiological processes. Results: The determination of 38 ligand/receptor contacts enabled the evidence-based modeling of a GPCR structure. Conclusion: The proposed GPCR structure assumes four interaction clusters with its ligand, which adopts a vertical binding mode. Significance: Elucidating the structure of GPCRs is central to their understanding and has several implications, e.g. rational drug design.

International Union of Basic and Clinical Pharmacology. XCIX. Angiotensin Receptors: Interpreters of Pathophysiological Angiotensinergic Stimuli

“…A two-step model for binding of AngII to AT 1 receptor has been proposed (Le et al, 2002;Feng et al, 2005). Boucard et al (2000) suggested an extended conformation of AT 1 receptorbound AngII (Perodin et al, 2002;Fillion et al, 2013). The methionine proximity mapping approach they used identified details of the residues lining the AngII binding (Correa et al, 2002;Clement et al, 2005Clement et al, , 2006Clement et al, , 2009.…”

Structural determinants for binding, activation, and functional selectivity of the angiotensin AT1 receptor

“…Ang II initially binds to ECL to induce a change in the ECL conformation to set a motion of ECLs to cause movements of the TM helices that in turn cause conformational changes in the cytoplasmic domain to initiate signal transduction . The involvement of the amino terminal and all three ECLs of the AT 1 receptor in the binding of Ang II suggest a relatively large surface area for the recognition of peptides (Fillion et al 2013 (Fillion et al 2010). Klco et al (2006) have identified a conserved structural motif, WPFG (Trp94, Pro95, Phe96, and Gly97) within the first ECL.…”

“…Disruption of both of the disulfide bonds nearly completely abolished Ang II binding to the AT 1 receptor, suggesting the contribution of the disulfide bonds to the maintenance of the binding conformation . The extracellular disulfide bridges in conjunction with a b-hairpin fold in ECL2 appeared to shape the entrance of the ligand-binding site by maintaining in close vicinity the residues of the ECL2 that are important for ligand binding and functions (Fillion et al 2013). ECL2 is the site for glycosylation.…”

“…Ang II binds the receptor at several sites in the extracellular loops (ECL) and transmembrane helices. The bound Ang II molecule adopts vertical binding mode with its amino terminus interacting across the ECL and its carboxy terminus interacting more deeply within the transmembrane domain (TMD) core (Fillion et al 2013). The ligand-binding pocket for the hormone is created with amino acid residues of transmembrane helices 2, 3, 4, 5, 6, and 7 (Boucard et al 2000, Baleanu-Gogonea & Karnik 2006.…”

“…Site-directed mutagenesis has led several investigators to suggest that amino acid residues 1-7 define receptor affinity, specificity, and initiation of signal transduction, whereas the amino acid 8 involves receptor agonism. Although non-Ang II peptide antagonists bind several binding sites similar to Ang II in the transmembrane helices, the biological activity of Ang II stems from unique binding sites on the receptor recognized by Ang II that occupies a more extensive area of the receptor than the non-peptide antagonist , Fillion et al 2013). …”