1. The luteinizing hormone receptor (LHR) mediates gonadal steroid hormone production in males and females. Specific mutations of the LHR gene in males cause a condition called testotoxicosis. These mutations are known to significantly increase the basal signaling level of LHR (constitutive activity). The three-dimensional structure of the backbone of the transmembrane bundle of LHR has been modeled from the 2D electron density map of bovine rhodopsin and other published data. The side chain rotamers of the resulting bundle were modeled using a conformational energy searching approach. Side chain interactions in models of wild-type and naturally occurring constitutively active mutant forms of LHR were compared. The comparisons suggest that single activating mutations perturb specific interactions of transmembrane helix 6 (TM6) with TM5 and TM7, either by disrupting the hydrophobic packing between TM5 and TM6, or by weakening H-bonds between TM6 and TM7. (With A. Shenker.) 2. Molecular modeling was used to predict the three-dimensional structures of a series of deoxyhypusine synthase inhibitors that are analogs of the enzyme's endogenous polyamine substrates. Three- dimensional structural comparisons were performed within and between groups of compounds characterized by a single variation in chemical structure (e.g. a shift in the position of a double bond along the chain) observed to strongly correlate with differences in IC50 values supplied by collaborators. Monte Carlo searching and energy minimization (MM2 force field) were used to predict the energetically preferred on formations of these flexible compounds in vacuo. The calculations resulted in between 80 and 3,300 minimum energy conformers per compound. The conformations of each compound were then superimposed and clustered into families. Clustering resulted in between 5 and 150 families per compound. Representative conformations from each family were compared between different compounds. The results of these comparisons suggest a qualitative correlation between conformational flexibility and IC50. Low IC50 values appear to be associated with compounds predicted to have fewer chain conformational families than those with high IC50 values. (With J. Folk and E. Wolff)
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