Allosteric Binding Illuminated?

G-protein coupled receptors are one of those areas that I used to think I understood, until I understood them better. These things are very far from being on/off light switches mounted in drywall - they have a lot of different signaling mechanisms, and none of them are simple, either. One of those that's been known for a long time, but remains quite murky, is allosteric modulation. There are many compounds known that clearly are not binding at the actual ligand site in some types of GPCR, but (equally clearly) can affect their signaling by binding to them somewhere else. So receptors have allosteric sites - but what do they do? And what ligands naturally bind to them (if any)? And by what mechanism does that binding modulate the downstream signaling, and are there effects that we can take advantage of as medicinal chemists? Open questions, all of them. There's a new paper in Nature that tries to make sense of this, and trying by what might be the most difficult way possible: through computational modeling. Not all that long ago, this might well have been a fool's errand. But we're learning a lot about the details of GPCR structure from the recent X-ray work, and we're also able to handle a lot more computational load than we used to. That's particularly true if we are David Shaw and the D. E. Shaw company, part of the not-all-that-roomy Venn diagram intersection of quantitative Wall Street traders and computational chemists. Shaw has the resources to put together some serio...
Source: In the Pipeline - Category: Chemists Tags: In Silico Source Type: blogs