Monday, 14 April 2008

British Crystallographic Association Spring Meeting

I spent Tuesday - Thursday of last week at the British Crystallographic Association Spring Meeting. The meeting has 4 strands Biological, Chemical, Industrial and Physical Crystallography.
Each contribute a plenary and then have their own separate sessions. The Biological Plenary was the Bragg Lecture where one famous crystallographer speaks about another usually older crystallographer and their work. This year Tony Crowther from the MRC Cambridge talked about his work and that of Michael Rossmann from Purdue University. Both made seminal contributions to the method of molecular replacement in protein crystallography. More on that in TSMB. Michael Rossmann when a postdoc for Max Perutz at the LMB in Cambridge was the first person to realise that the chains of hemoglobin looked like the chain of myoglobin and hence that you could solve structures of related proteins by molecular replacement. Michael then developed the mathematics and early software for molecular replacement. Tony Crowther did a Ph.D. with David Blow at the LMB and developed an improved form of the translation function. While working on natural language processing inEdinburgh, Tony also realised how to give a much faster and more acccurate version of the rotation function, which was the basis of the molecular replacement method for a long time. Tony's career was actually mainly in electron microscopy, he returned to the LMB from Edinburgh to work for Aaron Klug and became a group leader in his own right. Both he and Michael Rossmann have done most of their work on viruses and he talked about Michael's work on bacteriophage and his work on Hepatitis.
The Biological Group sessions were on Membrane proteins. Chris Tate from LMB in Cambridge described work they have been doing to stabilise membrane proteins by mutation. They search for alanine mutations that increase the stability of the protein in detergent and then carry out mutations in combination until the protein is stable for half an hour at a temperature 15-20 degrees hotter than the original. They have succeeded in crystallising beta-1 androgenic receptor, which will give important comparison to the beta-2 published just before Christmas.
The most interesting talk for me was from Thomas Sorenson, now at Diamond, on the work he and colleagues had done in the group of Poul Nissen in Aarhus. The group have published structures in several states of eukaryotic ATPase transproters (Calcium, sodium, proton). Interestingly these proteins were discovered by a Dane, Jens Skou and the group used proteins provided by various groups in Denmark that have worked on the systems for many years. They used natural sources and did not purify the proteins down columns, but just used differential extraction. This means that they isolated the membrane fraction that contained most of the protein and then extracted with detergents and this material was pure enough to crystallise in the presence of the right combination of detergents and lipids. The other biological sessions were on neutron diffraction, probing fast biological reactions, complementary methods, and ligand binding and drug design. Neutron diffraction gives the position of hydrogen atoms as both hydrogen and even more so deuterium diffract neutrons much more relatively than they do X-rays and you get density for hydrogen atoms. The catch is that neutron fluxes are much weaker and you need crystals that are 0.1- 1 mm3 compared to 0.0001 mm3 for a protein crystal. Studying reactions in crystals often means trapping intermediates by freezing out. Arwen Pearson from Leeds gave a good talk about a redox system that she had worked on in Minnesota where the reaction cycle can be carried out in the crystal, even changing space group between states. The catch, and this is common, is that X-rays themselves generate free radicals which can reduce redox centres so by collecting the data the redox state is altered. This meant that they had to collect data from several crystals before they became too damaged. The highlight for me of the Ligand and Drug session was a talk from Chris Phillips at Pfizer about their new non-nucleoside HIV Reverse Transcriptase inhibitor. These target a hydrophobic pocket in the protein, and tend to be rather 'greasy'. The Pfizer group had carefully designed a ligand that was both smaller and more hydrophilic and hence a better drug in terms of bioavailability.
There were many more great talks, but I hope this gives you a flavour of the meeting

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