Steric constraints, binding site

A similar scenario is assumed for Sup35p (Chien etal., 2004 Glover et al., 1997). The inactivation of Ure2p and by inference also of Sup35p in the prion states comes from steric constraints. One such mechanism would be steric blocking, that is, the binding sites for the interaction partners are not accessible in filaments. 

The change in structure along the lanthanide series, going from La3+ to Lu3+, can be ascribed to the decrease in ionic radius of the metal center which causes an increase of the rigidity and in the steric constraint on the water binding site [35,36]. For this reason the 9-coordinate Gd complex shows a remarkably high water exchange rate. 

D of protoporphyrin-IX depends on the steric constraints of the substrate binding pocket. Ortiz de Montellano (59) has used this selectivity to probe the active site structure of several heme enzymes. The structure of phenyl-cyt P-450cam has been determined by X-ray crystallography and indicates that N-phenyl heme formation is an accurate, low-resolution probe of active site structure. 

Araneda et al. tested 90 odorants for activity with the rat receptor 17 (70). They used an adenovirus to increase the level of 17 in the epithelium and to introduce green fluorescent protein (GFP) simultaneously as a way to detect activation. 17 was found to be very selective toward aldehydes and with a preference for eight carbon atoms in the chain. Both saturated and oleflnic aldehydes were found to be active and some tolerance exists for substituents, mostly methyl groups, on the chain. Using models, they could define more precisely the steric constraints on the binding site. 

The inclusion of the protein active site can add an important steric or shape constraint to the search, limiting the size of the selected molecules appropriately, as shown by application to the thyroid hormone receptor [75]. However, the real power of such methods comes from the ability to search receptor-based pharmacophores with only a limited user bias on the points to be used. This has been implemented via partial-match searching [103], available within UNITY, which marks a molecule as a hit if it matches 4 out of 20 possible pharmacophoric features in the site. Additional constraints on the solutions can be imposed by grouping the pharmacophore points and limiting matches to one or more points from each group, a feature of the THINK program [78]. In this way, molecules can be selected that explore several areas of the binding site. 

Early work with zinc metalloprotease inhibitors focused on the well-characterized agents captopril ((2S)-l-[(2S)-2-methyl-3-sulfanyl-propanoyl] pyrrolidine-2-carboxylic acid) and phos-phoramidon (/V-alpha-i,-rhamnopyranosyloxy[hydroxyphosphinyl -i,-leucyl-L-tryptophan). These compounds, however, were found to have little inhibitory activity against BoNT (Adler et al., 1994, 1999a). The poor efficacy of captopril was suggested to stem from unfavorable steric constraints in the binding of proline at the active site of BoNT (Schmidt and Stafford, 2002). 

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