Trp'ing the copper fantastic

The amino acid tryptophan has an unprecedented role in copper binding, suggests a study online this week in Nature Chemical Biology.

Copper is an essential metal for life. However, because it is highly reactive and therefore could cause damage to cells, it must be 'chaperoned' at all times. Relatively little is known about many of the proteins that move copper around cells. Thomas O'Halloran and colleagues looked closely at a copper trafficking protein called CusF. They found that a tryptophan from the CusF protein is very close to the copper and that the interaction between the tryptophan and the copper is critical for copper binding.

Tryptophan residues have been known to interact with positively charged ions, such as sodium or potassium, in what is called a 'cation-pi' interaction. These results now reveal that proteins can use these cation-pi interactions to delicately transport copper around cells.

Receptor signalling in pairs

Scientists have discovered new information about the way that small molecules cause cell signalling, according to a paper to be published online this week in Nature Chemical Biology. This insight could have major implications in regards to how drugs are developed.

G protein-coupled receptors, or GPCRs, are major drug targets because they bind to molecules that are outside the cell, and this binding causes big changes inside the cell. This means that a potential drug doesn't have to be able to cross the cell membrane to be active, which is simplifies the design of the drug.

Jean-Pierre Vilardaga and colleagues now find that, for some GPCRs that come together in pairs, the signaling by these pairs of receptors is different than signalling by a single receptor. This result will have particular relevance for scientists developing combination drugs, as the mixing of two individual small molecules may not cause the expected biological effect.

Compound screening gets more specific

A drug screening platform that can be used through the various testing and monitoring stages of the drug discovery process is reported online this week in Nature Chemical Biology.

High-throughput screening for drug candidates generally involves using enzymes purified from cells for use as the drug target, but whole cells are now being used more often. Garry Nolan and colleagues show that measurement of the phosphorylation levels of intracellular signalling proteins in whole cells could be extended from single drug effects to large-scale screening efforts. In their own screens, the authors identified several compounds that, from among all of the cell types and their associated signaling pathways found in whole blood, selectivity inhibited only the B cell Jak-Stat signalling pathway — the cytokine signaling pathway that mediates cell growth, differentiation, apoptosis, and other fundamental cell functions.

The strategy, called phospho flow, is therefore capable of screening compound libraries for inhibitors of specific kinase signalling pathways that target particular cell types in physiologically- and disease-relevant cell populations.

Cu(I) recognition via cation-π and methionine interactions in CusF

Yi Xue, Anna V Davis, Gurusamy Balakrishnan, Jay P Stasser, Benjamin M Staehlin, Pamela Focia, Thomas G Spiro, James E Penner-Hahn and Thomas V O'Halloran

Published online: 23 December 2007 | doi 10.1038/nchembio.2007.57

Abstract | Full text | PDF | Supplementary information

Conformational cross-talk between α_2A-adrenergic and μ-opioid receptors controls cell signaling

Jean-Pierre Vilardaga, Viacheslav O Nikolaev, Kristina Lorenz, Sébastien Ferrandon, Zhenjie Zhuang and Martin J Lohse

Published online: 13 January 2008 | doi 10.1038/nchembio.64

Abstract | Full text | PDF | Supplementary information

High-content single-cell drug screening with phosphospecific flow cytometry

Peter O Krutzik, Janelle M Crane, Matthew R Clutter and Garry P Nolan

Published online: 23 December 2007 | doi 10.1038/nchembio.2007.59

Abstract | Full text | PDF | Supplementary information