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J. Biol. Chem., Vol. 275, Issue 45, 35276-35280, November 10, 2000
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From the Department of Biochemistry and Molecular Biology, Medical
University of South Carolina, Charleston, South Carolina 29425
Relaxin has a unique, clearly identifiable, mixed
function receptor-binding region comprising amino acid residues that
evolve sequentially from the central portion of the B chain
The Relaxin Receptor-binding Site Geometry Suggests a Novel
Gripping Mode of Interaction*
-helix. Two arginine residues in positions B13 and B17 that project like forefinger and middle finger from the helix provide the electrostatic element opposed by the hydrophobic (thumb) element isoleucine (B20),
offset from the arginines by about 40°. The binding intensity of
relaxin to its receptor decreases by 3 orders of magnitude if alanine
is substituted for the newly discovered binding component isoleucine in
position B20. The arginine residues cannot be replaced by other
positive charges, nor can the guanidinium group be presented on a
longer or shorter hydrocarbon chain. In contrast, the hydrophobic interaction is incremental in nature, and the contribution to the total
binding energy is roughly proportional to the number of hydrocarbon
units in the side chain. It appears that a hydrophobic surface exists
on the receptor that offers optimal van der Waals' interaction with
-branched hydrophobic amino acids. The binding energy increases
roughly 10-fold with each methylene group whereby -branching is more
effective per surface unit than chain elongation. Aromatic side chains
appear to demarcate the extent of the binding region in so far as
residues larger than phenylalanine decrease receptor binding. The
exceptional clarity of binding site geometry in relaxin makes for an
excellent opportunity to design peptido-mimetics.
*
This work was supported by National Institutes of Health
Grant GM 48893.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: Dept. of Biochemistry
and Molecular Biology, Medical University of South Carolina, 173 Ashley
Ave., P.O. Box 250509, Charleston, SC 29425. Tel.: 843-792-9929; Fax:
843-792-4322; E-mail: schwabec@musc.edu.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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