An allosteric role for receptor activity-modifying proteins in defining GPCR pharmacology

G protein-coupled receptors are allosteric proteins that control transmission of external signals to regulate cellular response. Although agonist binding promotes canonical G protein signalling transmitted through conformational changes, G protein-coupled receptors also interact with other proteins. These include other G protein-coupled receptors, other receptors and channels, regulatory proteins and receptor-modifying proteins, notably receptor activity-modifying proteins (RAMPs). RAMPs have at least 11 G protein-coupled receptor partners, including many class B G protein-coupled receptors. Prototypic is the calcitonin receptor, with altered ligand specificity when co-expressed with RAMPs. To gain molecular insight into the consequences of this protein–protein interaction, we combined molecular modelling with mutagenesis of the calcitonin receptor extracellular domain, assessed in ligand binding and functional assays. Although some calcitonin receptor residues are universally important for peptide interactions (calcitonin, amylin and calcitonin gene-related peptide) in calcitonin receptor alone or with receptor activity-modifying protein, others have RAMP-dependent effects, whereby mutations decreased amylin/calcitonin gene-related peptide potency substantially only when RAMP was present. Remarkably, the key residues were completely conserved between calcitonin receptor and AMY receptors, and between subtypes of AMY receptor that have different ligand preferences. Mutations at the interface between calcitonin receptor and RAMP affected ligand pharmacology in a RAMP-dependent manner, suggesting that RAMP may allosterically influence the calcitonin receptor conformation. Supporting this, molecular dynamics simulations suggested that the calcitonin receptor extracellular N-terminal domain is more flexible in the presence of receptor activity-modifying protein 1. Thus, RAMPs may act in an allosteric manner to generate a spectrum of unique calcitonin receptor conformational states, explaining the pharmacological preferences of calcitonin receptor-RAMP complexes. This provides novel insight into our understanding of G protein-coupled receptor-protein interaction that is likely broadly applicable for this receptor class.

Annotated record of the detailed examination of Mn deposits from various ship expeditions in the Atlantic Ocean from 1876 until 1911

The greater part of this Monograph is devoted to detailed descriptions of 1426 samples of deposits from the floor of the Atlantic Ocean stored in the Challenger Office, Edinburgh, which had been collected during thirty-five cruising expeditions between 1857 and 1911. The remaining part discusses the results of the work. The work of examining and describing in detail this abundant mass of material was in progress when the late Sir JOHN MURRAY met his death in March 1914. By that time about three-fourths of the descriptive work had been completed under his supervision. Sir John's trustees arranged for the completion of the descriptive work by Mr Chumley, and this was done in the Challenger Office during the two succeeding years. Later, after he had removed to Glasgow, Mr Chumley prepared the notes discussing the results. The trustees have pleasure in recording, on the suggestion of Mr Chumley, the courtesy of Dr G. W. Lee of the Geological Survey of Scotland, for help in determining many of the rarer mineral particles contained in the deposits.

Core-level photoemission investigations of the CDTE(100) and INSB(100) surface and interfacial structures

Photoemission techniques, utilizing a synchrotron light source, were used to analyze the clean (100) surfaces of the zinc-blende semiconductor materials CdTe and InSb. Several interfacial systems involving the surfaces of these materials were also studied, including the CdTe(lOO)-Ag interface, the CdTe(lOO)-Sb system, and the InSb(lOO)-Sn interface. High-energy electron diffraction was also employed to acquire information about of surface structure. A one-domain (2xl) structure was observed for the CdTe(lOO) surface. Analysis of photoemission spectra of the Cd 4d core level for this surface structure revealed two components resulting from Cd surface atoms. The total intensity of these components accounts for a full monolayer of Cd atoms on the surface. A structural model is discussed commensurate with these results. Photoemission spectra of the Cd and Te 4d core levels indicate that Ag or Sb deposited on the CdTe(l00)-(2xl) surface at room temperature do not bound strongly to the surface Cd atoms. The room temperature growth characteristics for these two elements on the CdTe(lOO)-(2xl) are discussed. The growth at elevated substrate temperatures was also studied for Sb deposition. The InSb(lOO) surface differed from the CdTe(lOO) surface. Using molecular beam epitaxy, several structures could be generated for the InSb(lOO) surface, including a c(8x2), a c(4x4), an asymmetric (lx3), a symmetric (lx3), and a (lxl). Analysis of photoemission intensities and line shapes indicates that the c(4x4) surface is terminated with 1-3/4 monolayers of Sb atoms. The c(8x2) surface is found to be terminated with 3/4 monolayer of In atoms. Structural models for both of these surfaces are proposed based upon the photoemission results and upon models of the similar GaAs(lOO) structures. The room temperature growth characteristics of grey Sn on the lnSb(lOO)-c(4x4) and InSb(l00)-c(8x2) surfaces were studied with photoemission. The discontinuity in the valence band maximum for this semiconductor heterojunction system is measured to be 0.40 eV, independent of the starting surface structure and stoichiometry. This result is reconciled with theoretical predictions for heterostructure behavior.

The Hague, Netherlands, 1891 (Raster Image)

This layer is a georeferenced raster image of the historic paper map entitled: Nieuwste plan van 's Gravenhage : met de verschillende hieuwe bouwplannen, John C. Bignell graveur. It was published by John C. Bignell in 1891. Scale 1:10,000. Covers The Hague, Netherlands. Map in Dutch. The image inside the map neatline is georeferenced to the surface of the earth and fit to the 'RD_New (Rijksdriehoekstelsel), GCS Amersfoort' coordinate system. All map collar and inset information is also available as part of the raster image, including any inset maps, profiles, statistical tables, directories, text, illustrations, index maps, legends, or other information associated with the principal map. This map shows features such as roads, railroads and stations, street-railroads, drainage, canals, built-up areas and selected buildings, ground cover, parks, cemeteries, and more. Includes also index and advertisements in margins.This layer is part of a selection of digitally scanned and georeferenced historic maps from the Harvard Map Collection. These maps typically portray both natural and manmade features. The selection represents a range of originators, ground condition dates, scales, and map purposes.

Postal and telegraphic reforms /

"Reprinted from "The Contemporary Review," March, 1891".

Practical dispensing for students, pharmaceutical and medical.

Includes index.

...The principles and practice of early and infant school-education, with an appendix of infant-school hymns and songs with appropriate melodies.

Music : p. 285-310.

Lollardy and the reformation of England, an historical survey,

Vol. IV edited by William Hunt from manuscript which the author left "in an unfinished state." cf. Pref., vol. IV.

The chronicles of Greenford Parva; or, Perivale, past and present. With divers historical, archæological, and other notes, traditions, etc., relating to the church and manor, and the Brent Valley.

Mode of access: Internet.

Picture frame making for amateurs : being practical instructions in the making of various kinds of frames for paintings, drawings, photographs, and engravings /

Includes index.

English party leaders and English parties. From Walpole to Peel. Including a review of the political history of the last one hundered and fifty years.

v. 1. Sir Robert Walpole. William Pitt, earl of Chatham. Edmund Burke. Charles James Fox. William Pitt, pt.I.- v. 2. William Pitt, pt. II. George Canning. Sir Robert Peel.

The last American : a fragment from the journal of Khan-Li, prince of Dimph-Yoo-Chur and admiral in the Persian navy /

Mode of access: Internet.