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Submitted on February 10, 2003
Accepted on March 5, 2004
Dulbecco Telethon Institute and Department of Chemistry, University of Modena and Reggio Emilia, Modena, Italy. Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands
* To whom correspondence should be addressed. E-mail: fanelli{at}unimo.it.
In this study, molecular simulations have been combined with site-directed mutagenesis experiments to explore M398(2.43), a lutropin receptor (LHR) site in helix 2 susceptible to spontaneous activating mutations, and to develop a computational tool for predicting the functionality (i.e. active or non-active) of LHR mutants.
Site directed mutagenesis experiments engineered fifteen different substitutions for M389(2.43), which resulted in variable levels of constitutive activity, inversely correlated with the size of the replacing amino acid. This inverse correlation is suggested to be mediated by I460(3.46), M571(6.37) and Y623(7.53), the tyrosine of the NPxxY motif. In fact, size reduction at position 398(2.43), which is concurrent with constitutive receptor activity, releases the van der Waals interactions found in the wild type LHR between M398(2.43) and these three amino acids, resulting in structural modifications in the proximity to the E/DRY/W motif. An increment, above a threshold value, in the solvent accessibility of the cytosolic ends of helices 3 and 6 is the main structural feature shared by the active mutants of the LHR. This feature has been successfully used for predicting the functionality of the engineered mutants at M398(2.43), proving that molecular simulations can be useful for in silico screening of LHR mutants.
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