Allostery is the process by which biological macromolecules (mostly proteins) transmit the effect of binding at one site to another, often distal, functional site, allowing for regulation of activity. Recent experimental observations demonstrating that allostery can be facilitated by dynamic and intrinsically disordered proteins have resulted in a new paradigm for understanding allosteric mechanisms, which focuses on the conformational ensemble and the statistical nature of the interactions responsible for the transmission of information. Analysis of allosteric ensembles reveals a rich spectrum of regulatory strategies, as well as a framework to unify the description of allosteric mechanisms from different systems.

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The ensemble nature of allostery

The role of dynamics in allosteric regulation.

Although phenomenlogical models that account for cooperativity in allosteric systems date back to the early and mid-60's (e.g., the KNF and MWC models), there is resurgent interest in the topic due to the recent experimental and computational studies that attempted to reveal, at an atomistic level, how allostery actually works. In this review, using systems for which atomistic simulations have been carried out in our groups as examples, we describe the current understanding of allostery, how the mechanisms go beyond the classical MWC/Pauling-KNF descriptions, and point out that the “new view” of allostery, emphasizing “population shifts,” is, in fact, an “old view.” The presentation offers not only an up-to-date description of allostery from a theoretical/computational perspective, but also helps to resolve several outstanding issues concerning allostery.

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Allostery and cooperativity revisited.

From approximately the early 1980s, the “influence of natural products” upon drug discovery in all therapeutic areas apparently has been on the wane because of the advent of combinatorial chemistry technology and the “associated expectation” that these techniques would be the future source of massive numbers of novel skeletons and drug leads/new chemical entities (NCE) where the intellectual property aspects would be very simple. As a result, natural product work in the pharmaceutical industry, except for less than a handful of large pharmaceutical companies, effectively ceased from the end of the 1980s. What has now transpired (cf. evidence shown in Newman and Cragg, 2007 and Figures 1 and 2 below showing the continued influence of natural products as leads to or sources of drugs over the past 26 years (1981–2006)) is that, to date, there has only been one de novo combinatorial NCE approved anywhere in the world by the U.S. Food and Drug Administration (FDA) or its equivalent in other nations for any human disease, and that is the kinase inhibitor sorafenib (1, Chart 1), which was approved by the FDA in late 2005 for renal carcinoma. However, the techniques of combinatorial chemistry have revolutionized the deVelopment of active chemical leads where currently, instead of medicinal chemists making derivatives from scratch, a procedure is used whereby syntheses are based on combinatorial processes so that modifications can be made in an iterative fashion. An example of such a process would be the methods underlying the ultimate synthesis of the antibiotic linezolid (Zyvox, 2) by the Pharmacia (now Pfizer) chemists starting from the base molecules developed in the late 1980s by DuPont Pharmaceutical, who reported the underlying antibiotic activity and mechanism of action of this novel class of molecules, the oxazolidinones.

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M. F. Perutz

Papers

Stereochemistry of cooperative effects in hemoglobin.