Constructing And Evaluating Homology Models Of Other Receptor Types

Thus far, we have focused on the manipulation of crystal structures to describe receptor interactions with other antagonists and agonists, and conduct screening for novel modulators. However, in the vast majority of cases, a 3D model is desired for a GPCR with no available structure. For these receptors, computational modeling can indicate the amino acids lining the binding pocket cavity, suggest ligand/receptor interactions, and potentially allow screening for novel ligand chemotypes. GPCR conformational predictions must be carefully evaluated and interpreted with caution, as two previous eras of comparative modeling—the bacteriorhodopsin period from 1990 to 2000 and the 2000-2008 rhodopsin period—have demonstrated that the best available methods of structure prediction could not accurately capture the correct helical geometry and binding pocket shape for other GPCR types, let alone the conformation of ECL2 or other structurally variable regions [5]. Here we discuss relevant considerations in constructing and evaluating GPCR models for other receptor types and highlight several recent successes in the field.

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