Experimental aspects of SU(5)xU(1) supergravity

We study various aspects of $SU(5)\times U(1)$ supergravity as they relate to the experimental verification or falsification of this model. We consider two string-inspired, universal, one-parameter, no-scale soft-supersymmetry-breaking scenarios, driven by the $F$-terms of the moduli and dilaton fields. The model is described in terms of the supersymmetry mass scale (\ie, the chargino mass $m_{\chi^\pm_1}$), $\tan\beta$, and the top-quark mass. We first determine the combined effect on the parameter space of all presently available direct and indirect experimental constraints, including the LEP lower bounds on sparticle and Higgs-boson masses, the $b\to s\gamma$ rate, the anomalous magnetic moment of the muon, the high-precision electroweak parameters $\epsilon_1,\epsilon_b$ (which imply m_t\lsim180\GeV), and the muon fluxes in underground detectors (neutrino telescopes). For the still-allowed points in $(m_{\chi^\pm_1},\tan\beta)$ parameter space, we re-evaluate the experimental situation at the Tevatron, LEPII, and HERA. In the 1994 run, the Tevatron could probe chargino masses as high as 100 GeV. At LEPII the parameter space could be explored with probes of different resolutions: Higgs boson searches, selectron searches, and chargino searches. Moreover, for m_t\lsim150\GeV, these Higgs-boson searches could explore all of the allowed parameter space with \sqrt{s}\lsim210\GeV.Comment: latex, 36 pages, 25 figures (not included). Figures are available via anonymous ftp from hplaa02.cern.ch (/pub/lopez) as either 33 ps files (Easpects*.ps, 8.1MB) or one uuencoded file (AllFigures.uu, 3.7MB

Structural basis for bifunctional peptide recognition at human δ\delta-opioid receptor

Bifunctional μ- and ​δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human ​δ-OR bound to the bifunctional ​δ-OR antagonist and ​μ-OR agonist tetrapeptide ​H-Dmt-Tic-Phe-Phe-NH2 (​DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between ​H-Dmt and ​Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics

Human GLP-1 receptor transmembrane domain structure in complex with allosteric modulators

The glucagon-like peptide-1 receptor (GLP-1R) and the glucagon receptor (GCGR) are members of the secretin-like class B family of G-protein-coupled receptors (GPCRs) and have opposing physiological roles in insulin release and glucose homeostasis. The treatment of type 2 diabetes requires positive modulation of GLP-1R to inhibit glucagon secretion and stimulate insulin secretion in a glucose-dependent manner. Here we report crystal structures of the human GLP-1R transmembrane domain in complex with two different negative allosteric modulators, PF-06372222 and NNC0640, at 2.7 and 3.0 Å resolution, respectively. The structures reveal a common binding pocket for negative allosteric modulators, present in both GLP-1R and GCGR and located outside helices V-VII near the intracellular half of the receptor. The receptor is in an inactive conformation with compounds that restrict movement of the intracellular tip of helix VI, a movement that is generally associated with activation mechanisms in class A GPCRs. Molecular modelling and mutagenesis studies indicate that agonist positive allosteric modulators target the same general region, but in a distinct sub-pocket at the interface between helices V and VI, which may facilitate the formation of an intracellular binding site that enhances G-protein coupling

Structural basis for bifunctional peptide recognition at human δ-opioid receptor

Bifunctional μ- and ​δ-opioid receptor (OR) ligands are potential therapeutic alternatives, with diminished side effects, to alkaloid opiate analgesics. We solved the structure of human ​δ-OR bound to the bifunctional ​δ-OR antagonist and ​μ-OR agonist tetrapeptide ​H-Dmt-Tic-Phe-Phe-NH2 (​DIPP-NH2) by serial femtosecond crystallography, revealing a cis-peptide bond between ​H-Dmt and ​Tic. The observed receptor-peptide interactions are critical for understanding of the pharmacological profiles of opioid peptides and for development of improved analgesics