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J Biol Chem, Vol. 275, Issue 8, 5682-5686, February 25, 2000
From the Division of Physical Biochemistry, MRC National Institute
for Medical Research, The Ridgeway, Mill Hill,
London NW7 1AA, United Kingdom
Activation of the rhodopsin-like 7-transmembrane
(7-TM) receptors requires switching interhelical constraints that
stabilize the inactive state to a new set of contacts in the activated
state, which binds the cognate G-protein. The free energy to drive this is provided by agonist binding, which has higher affinity to the active
than to the inactive conformation. We have sought specific interhelical
constraint contacts, using the M1 muscarinic
acetylcholine receptor as a model. Histidine substitutions of
particular groups of amino acids, in transmembrane domains 3, 6, and 7, created high-affinity Zn2+ binding sites, demonstrating the
close proximity of their side chains in the inactive state. Alanine
point substitutions have shown the effect of weakening the individual
intramolecular contacts. In each case, the acetylcholine affinity was
increased, implying promotion of the activated state. These amino acids
are highly conserved throughout the 7-TM receptor superfamily. We
propose that they form an important part of a network of conserved
interhelical contacts that defines the off-state of a general
transmembrane switch mechanism.
A Network of Conserved Intramolecular Contacts Defines the
Off-state of the Transmembrane Switch Mechanism in a
Seven-transmembrane Receptor*
and
*
This work was supported by the Medical Research Council,
United Kingdom.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed. Tel.:
44 181-959-3666; Fax: 44 181-906-4477; E-mail:
zlu@nimr.mrc.ac.uk.
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