I couldn’t let today pass without writing something about the Nobel prize. Before long I’ll write a full piece about G protein-coupled receptors (GPCRs) but that’s quite a big story. For now, I just want to stress their importance and their place in current research.
A cell requires isolation from the outside world; maintaining different concentrations of ions inside and outside the cell is a vital part of how it functions. GPCRs play a hugely important role in detecting signals sent from outside the cell and relaying them to the inside. They are known as trans-membrane proteins because they extend from outside the cell, through the membrane and into the inner region. This means that when they bind a ligand on the outside of the cell (e.g. a hormone), the resulting structural rearrangement can trigger a chain of signals through to the inner machinery of the cell.Trans-membrane proteins are poorly studied, largely because it is so difficult to keep them stable when studying them in the lab. The parts of the protein that are outside the membrane will have positive and negative charges pointed outwards, interacting with water molecules. However, the membrane is made from fatty chains that repel water and so the region of the protein that stays in the membrane will be structured in a way that avoids water by having its hydrophobic amino acids pointing outwards. Keeping both of these regions stable in the same solution is tricky, but manageable. Detergents can mimic the membrane and are widely used.
Detergents can make it difficult to study the structure of GPCRs. Most protein structures are solved using X-ray crystallography or nuclear magnetic resonance (NMR). However, crystallography requires all the protein molecules to be very uniform which is difficult with the added complexity of a detergent that may form different shapes and sizes. NMR begins to lose its sensitivity as the size of the protein increases. In this case, the detergent counts towards the protein’s size which makes it difficult to get data.
This has meant that despite the huge importance of GPCRs in biochemistry and medicine (over a third of all drugs act via GPCRs), our understanding of them is still relatively poor. However we would be a lot further behind if it wasn’t for Lefkowitz and Kobilka – they are very deserving Nobel laureates.