Institute of Membrane & Systems Biology - Faculty of Biological ...

Dan Donnelly
BSc Biological Chemistry, University of Leicester (1988)
PhD, University of London 1992, supervisor Prof TL Blundell
Post doc with Prof J.B.C. Findlay (1991-1995)
Lecturer (1995-2004) & Senior Lecturer (2004-), University of Leeds
Contact: d.donnelly@leeds.ac.uk
G Protein-Coupled
Receptors
My research group studies the structure
& function of G protein-coupled
receptors - one of the most diverse
and ubiquitous families of integral
membrane proteins. GPCRs play a
pivotal role in many cellular signalling
pathways and are prime targets for
the development of therapeutic agents
designed to either block or activate the
receptors. The aim of this laboratory is
to elucidate the mechanism by which
these receptors bind their ligands
and transduce the signal across the
plasma membrane.
The control of the body’s blood sugar
level requires keeping an intricate
balance between the levels and
actions of the two opposing pancreatic
hormones, insulin and glucagon. While
low glucose levels result in glucagon
secretion from pancreatic alpha cells, in
the high glucose situation the action of
glucose on pancreatic beta cells results
in increased plasma insulin levels.
However, high blood glucose levels are
not solely responsible for increased
insulin secretion. Two hormones,
glucagon-like peptide-1 (GLP-1) and
glucose-dependent-insulinotropic
polypeptide (GIP), are responsible
sensing food intake and consequently
sensitizing the pancreatic beta cells’
insulin secretory system to glucose.
Using truncated and mutated receptors
alongside modified peptide ligands, our
group has defined a two-stage model for
peptide binding at the GLP-1 receptor
(Al-Sabah & Donnelly, 2003; Lopez de
Maturana et al. 2003).
The GLP-1 work in my laboratory
is currently funded by an Industrial
Partnership award from BBSRC &
AstraZeneca, part of which involves
the design & synthesis of small
molecules ligands (Dr. Colin Fishwick,
School of Chemistry).
As part of a collaboration with GSK, our
group also study the calcitonin receptorlike
receptor (e.g. Miller et al., 2010) and
the receptors for parathyroid hormone
(e.g. Mann et al., 2008).
Current Funding: BBSRC; GSK,
AstraZeneca
Past Funding: Novo Nordisk, Knoll, Royal
Society, BBSRC, Wellcome
Trust, British Heart Foundation
and Diabetes UK.
More information:
www.fbs.leeds.ac.uk/staff/profile.
php?staff=DD
Figure 1: Schematic figure of how GLP-1 bind to its
receptor (left) and a competition binding experiment
using three different ligands at the GLP-1 receptor
expressed in HEK-293 cells (right).
Representative Publications
Mann RJ, Nasr NE, Sinfield JK, Paci E, Donnelly
D (2010) The major determinant of exendin-4/
GLP-1 differential affinity at the rat GLP-1
receptor N-terminal domain is a hydrogen bond
from SER-32 of exendin-4. Brit. J. Pharmacol doi:
10.1111/j.1476-5381.2010.00834.x
Miller PS, Barwell J, Poyner DR, Wigglesworth
MJ, Garland SL, Donnelly D (2010) Non-peptidic
antagonists of the CGRP receptor, BIBN4096BS
and MK-0974, interact with the calcitonin
receptor-like receptor via methionine-42 and
RAMP1 via tryptophan-74. Biochem Biophys Res
Commun 391(1): 437-442
Mann R, Wigglesworth MJ, Donnelly D (2008)
Ligand-receptor interactions at the parathyroid
hormone receptors: subtype binding selectivity is
mediated via an interaction between residue 23
on the ligand and residue 41 on the receptor. Mol
Pharmacol 74(3): 605-613
Al-Sabah S, Donnelly D (2003) A model for
receptor-peptide binding at the glucagon-like
peptide-1 (GLP-1) receptor through the analysis
of truncated ligands and receptors British Journal
of Pharmacology 140: 339-346
Lopez de Maturana R, Willshaw A, Kuntzsch
A, Rudolph R, Donnelly D (2003) The isolated
N-terminal domain of the glucagon-like
peptide-1 receptor binds exendin peptides
with much higher affinity than GLP-1 Journal of
Biological Chemistry 278: 10195-10200