Computer-generated structural models of GPCR's based on the
crystal structure of rhodopsin have allowed the Sakmar Lab
to study specific receptor-drug interactions with the aim of
improving the design and synthesis of new drugs with higher
potency and fewer side effects. For example, the virus that
causes AIDS, HIV, hijacks a GPCR found on lymphocytes, the
chemokine receptor CCR5, to gain entry into the cell. A new
class of drugs designed to bind to the chemokine receptor and
block HIV cellular entry is being developed using knowledge
of GPCR biology. We are studying the structure of the
chemokine receptor and how it is modified by cellular enzymes
during its biosynthesis.
A model of the CCR5 receptor is shown from within the plane
of the cell membrane (left) and from above (right).
CCR5 is
a GPCR with seven transmembrane helices (cyan ribbons) and is
a molecular relative of rhodopsin. In collaboration with
Tanya Dragich (Albert Einstein College of Medicine) and John
P. Moore (Weill Medical College of Cornell University), we
replaced each amino acid shown in space-filling representation
with alanine to determine its effect on the activity of a small
molecule drug that inhibits HIV entry into cells. The data
suggested that the CCR5 inhibitor TAK-779 binds red amino acids
primarily and orange and yellow residues to a lesser extent.
Replacement of dark blue residues had no substantial effect on
drug binding, and replacement of light blue residues caused CCR5
expression problems and could not be tested. The work identified
sites where mutations prevented the ability of TAK-779 to inhibit
HIV binding. This functional binding site must be related to the
surface of the receptor that makes physical contact with bound
TAK-779.
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