 The last major concept class of transport is not really transport at all because we're not transporting molecules, but it's signaling. That rhodopsin molecule I showed, this particular one is bacterial rhodopsin, but it's closely related to the rhodopsin molecule in our eyes. And what happens in our eyes is that something is translated from light into nerve signals, right? The way that happens is that you have a molecule with a so-called retinal bound. So it's a rhodopsin that looks like this, and in the middle of this protein we have a small organic compound bound. That compound has a double bond in the middle that is normally in cis configuration, but when light hits this compound it switches over to a transconformation. And that transconformation causes the entire protein to change shape a little bit, and then it's bound to another protein, a so-called G-protein, sitting on the other side which then lets off as cascade. And here you can even see the reaction here. So on the left you have the cis conformation, and a photon strikes that. A photon strikes that, turns it into a trans, a higher energy state. This higher energy state induces a conformation transition in the membrane that is coupled to the G-protein, and that eventually creates the nerve signal that makes Rc. A protein that is kind of a receptor for something that is coupled to a G-protein is typically called G-protein-coupled receptor. G-p-c-r. I'll draw that down here. G-p-c-r. It's an exceptionally important class of proteins. And we were quite excited when we first got this bacterial rhodopsin structures in the 1980s, because people then assumed that now we can determine structures of all these GPCRs, we will understand everything about signaling. And then the years went by, and went by. And we eventually started getting structures of ion channels, but it proved to be pretty much impossible to determine structures of GPCRs. I bet there have been billions of dollars that were invested in that and not much happening. But science works that way. Sometimes it goes slow, and then from one day to another, things happen. Suddenly Ray Stevens and Brian Kubilke were able to determine structures of G-protein-coupled receptors. And from one day to another, that meant when we had one structure, we could repeat that recipe and get structure one more and one more. This has exploded since. It's arguably one of the most important classes of targets for the pharmaceutical industry. Occasionally we say that in the ballpark of half of the important targets for the pharma industry are membrane proteins. Technically that's true, but I would say that the vast majority of those targets are actually GPCRs. Because if we can change signaling, we can change how cells behave. And the up-and-coming part is likely ion channels. So one way or another we would like to understand what happens if this protein is binding something on the outside. Because most of them do not respond to photons, but a small chemical molecule binding. And how is that then translated to this G-protein on the inside? I showed you such one movie at the first lecture, but we're going to show it to you again just to show how fun it is. This is run by Ron Drawer on one of those high-end special-purpose computers in New York. So do you see the time scale up on the left? Compare that to the simulations you're running in the lab. Initially this is going to be slow and then we will speed it up. And then we have this small compound on the outside. And have a look at how the structure is changing. Here we go. One, two, three. So first this is relatively slow. We're just talking nanoseconds here. Half a microsecond there. Now it's binding. And now you're starting to see some local conformational changes. And at some point here, now we speed up a lot. Two, three, four microseconds. We're going to go to 25. This is changing the entire conformation of the helices and eventually you saw one of the helices move out. In this particular case, we only had the central part of the channel. But this helix moving out is what's going to create the chain effect with the entire interior part of the protein, causing something to happen on the inside of the cell. And exactly what happens depends a bit on what GPCR we're looking at. So I used to keep an updated list of these GPCRs in this class, but it's hopeless and would be outdated every single year. So we went from when I was a student to having this as a faint hope that maybe one day we might have one structure or possibly start to get some indirect insight of them. Today we have dozens of structures. So this is a phylogenetic tree of all, a tree of all the GPCRs we know. And you can see how this has been exploding just the last few years. And for many of these we now have structures both in an activated and inactivated states with the various compounds bound and everything. So we're starting to understand maybe not everything about this channel, but we know a whole lot more that is going to help us to do drug design.