Knowledge homology modeling

MJ Sutcliffe, I Haneef, D Carney, TL Blundell. Knowledge based modelling of homologous proteins. Part I Three dimensional frameworks derived from the simultaneous superposition of multiple structures. Protein Eng 1 377-384, 1987. 

MJ Sutcliffe, ERE Hayes, TL Blundell. Knowledge based modeling of homologous proteins. Part II Rules for the conformation of substituted side-chains. Protein Eng 1 385-392, 1987. 

Knowledge about receptor structure and receptor-ligand interactions, for example, homology models. X-ray and/or NMR structures, thermodynamics of ligand binding, effect of point mutations and dynamic motions of receptor and ligands. 

Knowledge-based model combining sequence data to other information, such as homology modeling (Hilbert et ah, 1993 Chinea et al., 1995). 

This study was based on a model of the outer vestibule, which was developed using indirect evidence like the structure of known ligands and data from mutational analysis. At that time, the KcsA crystal structure or other potassium channel X-ray structures were not available. Meanwhile, more detailed knowledge of the atomic details of potassium channels allows the development of homology models [47] that can be successfully used in drug design, as demonstrated by the following example. 

Sutcliffe, M. J., Hayes, F. R. F., Blundell, T. L. Knowledge-based modelling of homologous proteins, part II Rules for the conformations of substituted sidechains. Protein Engineering, 1987, 1,385-392. 

The premise underpinning homology modeling arises from the observation that proteins with similar amino acid sequences have a tendency to adopt similar 3D structures [1]. Therefore it is possible to predict the 3D structure of a protein based solely on knowledge of its amino acid sequence and the 3D structures of proteins with similar sequences. 

The very likely presence in the sweet taste receptor of cavities similar to those hosting Glu in mGluRl, a metabotropic glutamate receptor of known structure (Kunishima et al., 2000), tells us that the sweet taste of small molecular weight sweeteners can certainly be accounted for, even if the details will remain in part obscure, at least till a receptor structure with better resolution than homology models will be available. Can the taste of sweet proteins be also explained by the knowledge of the receptor There is no obvious answer. Let us first examine possible receptor models in detail. 

---