Structure-function relationship ligands

Moreover, molecular modeling is one key method of a wide range of computer-assisted methods to analyze and predict relationships between protein sequence, 3D-molecular structure, and biological function (sequence-structure-function relationships). In molecular pharmacology these methods focus predominantly on analysis of interactions between different proteins, and between ligands (hormones, drugs) and proteins as well gaining information at the amino acid and even to atomic level. 

The aim of the second dimension depth is to consider protein 3D-stmctures to uncover structure-function relationships. Starting from the protein sequences, the steps in the depth dimension are structure prediction, homology modeling of protein structures, and the simulation of protein-protein interactions and ligand-complexes. 

As to the functional role of sFas variants, there have been several reports based on apoptosis inhibition tests (Cl, Jl, L6, PI). According to these smdies, all sFas variants observed in normal donors are able to block the apoptosis induced by either an agonistic antibody or the natural Fas ligand in Fas-positive cells. Injection of sFas into mice significantly alters lymphocyte development (C3). Although the functional machinery remains controversial, Papoff et al. (PI) have proposed an attractive hypothetical model of structure/function relationships for the Fas molecule, as shown in Fig. 5. This model appears to be supported by the fact that all sFas variants have N-terminal ends containing the activation domain of 49 amino acids, which is required for proximal Fas ligand-mediated events. 

Fig. 5. A hypothetical model of the structure/function relationship between wild-type mFas and sFas variants. A requirement for the normal signahng process is to form homotrimers of the complete mFas molecules. sFas can also trimerize with wild-type mFas, suggesting that such an aberrant trimerization results in disruption of the signahng. Fas-L, Fas ligand DD, death domain aa, amino acid.

Darensbourg MY, Tuntulani T, Reibenspies JH (1995) Structure/function relationships in ligand-based S02/02 conversion to sulfate as promoted by nickel and palladium thiolates. Inorg Chem 34 6287-6294... 

Clark-Lewis, 1., Mattioli, 1., Gong, J. H., and Loetscher, P. (2003). Structure-function relationship between the human chemokine receptor CXCR3 and its ligands. /. Biol. Chem. 278, 289-295. 

These reactions can be used to understand many of the structure-function relationships among the approved drugs and those that have undergone clinical testing. For example, carboplatin retains the cis -diammineplatinum(II) center, but the chlorides have been replaced by the cyclobutanedicarboxylate ligand. The similar array of... 

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