Noble metals strip peptides from class II MHC proteins
Nature Chemical Biology
Published online: 26 February 2006 | doi:10.1038/nchembio773
Stephen L De Wall1,2,6,8, Corrie Painter3, Jennifer D Stone4, Rajintha Bandaranayake3, Don C Wiley5,7, Timothy J Mitchison1,2, Lawrence J Stern3,4 and Brian S DeDecker1,8
Class II major histocompatibility complex (MHC) proteins are essential for normal immune system function but also drive many autoimmune responses. They bind peptide antigens in endosomes and present them on the cell surface for recognition by CD4+ T cells.
A small molecule could potentially block an autoimmune response by disrupting MHC-peptide interactions, but this has proven difficult because peptides bind tightly and dissociate slowly from MHC proteins. Using a high-throughput screening assay we discovered a class of noble metal complexes that strip peptides from human class II MHC proteins by an allosteric mechanism.
Biochemical experiments indicate the metal-bound MHC protein adopts a 'peptide-empty' conformation that resembles the transition state of peptide loading. Furthermore, these metal inhibitors block the ability of antigen-presenting cells to activate T cells.
This previously unknown allosteric mechanism may help resolve how gold(I) drugs affect the progress of rheumatoid arthritis and may provide a basis for developing a new class of anti-autoimmune drugs.
http://www.nature.com/nchembio/journal/ ... io773.html
Plus there's an article about the above letter in "The Economist", and here's an excerpt...
Dr DeDecker and his colleagues have been searching for many years for drugs that will disrupt the activity of molecules called MHC class II proteins. The immune system works using special “antigen-presenting” cells armed with these proteins to present pieces of an invading bacterium or virus on their surfaces to other cells known as lymphocytes. This presentation tells the lymphocytes what they should be looking for, rather in the way that allowing a bloodhound to smell a piece of clothing lets it track a suspect. In those with autoimmune diseases something goes wrong with the recognition system and the lymphocytes start seeking out and destroying the wrong cells, so it is reasonable to suspect that MHC class II proteins might be implicated.
During the course of their search, Dr DeDecker and his team have screened some 30,000 chemical compounds in the hope of finding something that might adversely affect the proteins in question, without much success. But that was before they decided to screen a group of drugs that had recently been approved for other purposes. Two of these drugs worked, and they had a surprising element in common: platinum.
Initially Dr DeDecker was less than pleased. “We were looking for a fancy, complex organic molecule and found something simple instead,” he explains. But he soon rallied. The group then went on to discover that it was not just platinum that disrupted the work of the MHC class II proteins. The whole class of noble metals (so called because they are snobbishly unreactive with other elements) behaved in this way. In particular, Dr DeDecker found that besides platinum, palladium and gold worked especially well. The researchers still do not understand completely how these metals disrupt MHC class II proteins, but the speed with which that disruption happens suggests that the metal atoms are actively knocking crucial pieces of the system out.
http://www.economist.com/science/displa ... id=5572498
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