Molecular basis for selectivity

R., and Crews, C. M. Crystal structure of epoxomidn 20S proteasome reveals a molecular basis for selectivity of alpha, beta -epoxyketone proteasome inhibitors. J. Am. Chem. Soc. 2000b, 122, 1237-1238. 

This chapter briefly reviews the present understanding of the chemistry, origin, and distribution of the saxitoxins and methods for their detection. The second section of this chapter discusses studies on their pharmacology directed toward an understanding of the molecular basis for their strong, highly selective interaction with the sodium channel binding site. 

In neurons and non-neuronal cells, kinesin is associated with a variety of MBOs, ranging from synaptic vesicles to mitochondria to lysosomes. In addition to its role in fast axonal transport and related phenomena in non-neuronal cells, kinesin appears to be involved in constitutive cycling of membranes between the Golgi and endoplasmic reticulum. However, kinesin is not associated with all cellular membranes. For example, the nucleus, membranes of the Golgi complex and the plasma membrane all appear to lack kinesin. Kinesin interactions with membranes are thought to involve the light chains and carboxyl termini of heavy chains. However, neither this selectivity nor the molecular basis for binding of kinesin and other motors to membranes is well understood. 

Recapitulating the foregoing discussion, it is clearly not our opinion that solution experiments appear to be inadequate for the purpose of comparison with molecular theories. However, we want to point out that due to the evident shortcomings of present theoretical and computational facilities a distinct scepticism is necessary in order to avoid the production of meaningless data. Of course, the solution experiments remain the main source of information, the data of which must be explained by theory. At the present stage of knowledge it is only possible to pick out selected properties of solutions which can be described satisfactorily on a molecular basis. For instance, referring to Frank and Wen s model of solvation shells W, the structure of the inner shell should not be modified too much by... 

Poux, A.N. and Marmorstein, R. (2003) Molecular basis for Gcn5/PCAE histone acetyltransferase selectivity for histone and nonhistone substrates. Biochemistry, 42 (49), 14366-14374. 

Karlsson JG, Andersson LI, Nicholls lA. Probing the molecular basis for ligand-selective recognition in molecularly imprinted polymers selective for the local anaesthetic bupivacaine. Anal Chim Acta 2001 435 57-64. 

Fong TM, Yu H, Strader CD (1992) Molecular basis for the species selectivity of the neurokinin-1 receptor antagonists CP-96,345 and RP67580. J Biol Chem 267 25668-25671... 

Seaman, F.C. Hurley, L.H. (1998) Molecular basis for the DNA sequence selectivity of ecteinascidin 736 and 743 evidence for the dominant role of direct readout via hydrogen bonding. J. Am. Chem. Soc., 120, 13028-41. 

The Molecular Basis for Sensitivity of EGFR Mutants to Selective TKIs... 

Topal, M. D., Di Guiseppi, S. R., and Sinha, N. K. (1980). Molecular basis for substitution mutations Effect of primer terminal and template residues on nucleotide selection by phage T4 DNA polymerase in vitro. J. Biol. Chem. 255, 11717-11724. 

Pheromones are powerful modulators of insect behavior. Since the isolation and identification of the first pheromone, (10E, 12Z)-hexadec-10,12-dien-l-ol, the sex attractant of the silk moth Bombyx mori, thousands of other insect pheromones have been identified. Our understanding of the sensory apparatus required for pheromone detection has also increased significantly. Coincidentally, B. mori was instrumental in many of these advances (see below). Volatile pheromones are detected by a specialized olfactory system localized on the antennae. The precise recognition of species-specific nuances in the structure and composition of pheromone components is essential for effective pheromone-based communication. The pheromone olfactory system of species studied so far exhibits remarkable selectivity towards the species-specific pheromone blend. Pheromones are emitted in low (fg-pg) quantities and are dispersed and greatly diluted in air plumes. Thus, pheromone olfaction systems are among the most sensitive chemosensory systems known. (Schneider et al., 1968). This chapter summarizes efforts (particularly over the past 10 years) to understand the molecular basis for the remarkable selectivity and sensitivity of the pheromone olfactory system in insects. The chapter will also outline efforts to design compounds that interfere with one or more of the early events in olfaction. 

The molecular basis for the evolution of distinct kdr mutations in different insects and arachnids remains unclear. Assuming that the pyrethroid binding site(s) (and/or the pyrethroid response domain) is composed of multiple amino acid residues, there are two ways by which different mutations can be selected in different insects and arachnids. First, the random mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity without impacting normal sodium channel functional properties. Thus, selection of different mutations in different insects and arachnids is purely random. Second, the nonrandom mutation hypothesis mutation in any pyrethroid binding site/response domain affects pyrethroid toxicity, but some mutations also drastically alter normal sodium channel functional properties in one species, but not in another, presumably because of different sodium channel backbone sequences. That is, there may be severe fimess costs for some mutations, if placed out of their native protein context. 

A close structural analog of the non-selective COX inhibitor diclofenac, lumiracoxib displays a 500-fold greater selectivity for COX-2 than COX-1 in vivo and exhibits a unique pharmacologic profile that includes rapid absorbance and a relatively short plasma half-life (41, 42). Lumiracoxib lacks the tricyclic structure of the diarylheterocycle class of COX-2 selective inhibitors (e.g., celecoxib and rofecoxib) and does not contain a sulfonamide or sulfone group. Although structurally related, lumiracoxib and diclofenac exhibit large differences in the selectivity of COX-2 inhibition, and the molecular basis for this... 

The experiments described here were initiated to explore the molecular basis for the half-site spacing selectivity of CREB/ATF proteins. We prepared a series of seven test peptides in which the basic, spacer, and zipper segments of GCN4... 

Kotler-Brajtburg J, Price HD, Medoff G,etal. Molecular basis for the selective toxicity of amphotericin B for yeast and filipin for animal cells. Antimicrob Agents Chemother 1974 5 377-82. 

---