3 results for Archbold, JK

  • Identification of key residues involved in adrenomedullin binding to the AM1 receptor

    Watkins, Harriet; Au, M; Bobby, R; Archbold, JK; Abdul-Manan, N; Moore, JM; Middleditch, Martin; Williams, Geoffrey; Brimble, Margaret; Dingley, Andrew; Hay, Deborah (2013-05)

    Journal article
    The University of Auckland Library

    Adrenomedullin (AM) is a peptide hormone whose receptors are members of the class B GPCR family. They comprise a heteromer between the GPCR, the calcitonin receptor-like receptor and one of the receptor activity-modifying proteins 1-3. AM plays a significant role in angiogenesis and its antagonist fragment AM22-52 can inhibit blood vessel and tumour growth. The mechanism by which AM interacts with its receptors is unknown.

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  • Structural insights into RAMP modification of secretin family G protein-coupled receptors: implications for drug development.

    Archbold, JK; Flanagan, Jack; Watkins, HA; Gingell, Joseph; Hay, Deborah (2011-10)

    Journal article
    The University of Auckland Library

    Secretin family G protein-coupled receptors (GPCRs) are important therapeutic targets for migraine, diabetes, bone disorders, inflammatory disorders and cardiovascular disease. They possess a large N-terminal extracellular domain (ECD) known to be the primary ligand-binding determinant. Structural determination of several secretin family GPCR ECDs in complex with peptide ligands has been achieved recently, providing insight into the molecular determinants of hormone binding. Some secretin family GPCRs associate with receptor activity-modifying proteins (RAMPs), resulting in changes to receptor pharmacology. Recently, the first crystal structure of a RAMP ECD in complex with a secretin family GPCR was solved, revealing the elegant mechanism governing receptor selectivity of small molecule antagonists of the calcitonin gene-related peptide (CGRP) receptor. Here we review the structural basis of ligand binding to secretin family GPCRs, concentrating on recent progress made on the structural basis of RAMP-modified GPCR pharmacology and its implications for rational drug design.

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  • Calcitonin and Calcitonin Receptor-Like Receptors: Common themes with family B GPCRs

    Barwell, J; Gingell, JJ; Watkins, HA; Archbold, JK; Poyner, D; Hay, DL (2011)

    Journal article
    The University of Auckland Library

    The calcitonin receptor (CTR) and calcitonin-like receptor (CLR) are two of the fifteen human family B (or Secretin-like) G protein-coupled receptors (GPCRs). CTR and CLR are of considerable biological interest as their pharmacology is moulded by interactions with receptor activity-modifying proteins (RAMPs). They also have therapeutic relevance for many conditions, such as osteoporosis, diabetes, obesity, lymphatic insufficiency, migraine and cardiovascular disease. In light of recent advances in understanding ligand docking and receptor activation in both the family as a whole and in CLR and CTR specifically, this review reflects how applicable general family B GPCR themes are to these two idiosyncratic receptors. We review the main functional domains of the receptors; the N-terminal extracellular domain, the juxtamembrane domain and ligand interface, the transmembrane domain and the intracellular C-terminal domain. Structural and functional findings from the CLR and CTR along with other family B GPCRs are critically appraised to gain insight into how these domains may function. The ability for CTR and CLR to interact with RAMPs adds another level of sophistication to these receptor systems but means careful consideration is needed when trying to apply generic GPCR principles. This review encapsulates current thinking in the realm of family B GPCR research by highlighting both conflicting and reccurring themes and how such findings relate to two unusual but important receptors, CTR and CLR.

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