European researchers have used computers to find proteins that bind a receptor linked to prostate cancer.

Luc Brunsveld, of the Eindhoven University of Technology, and colleagues from the Netherlands and Germany have used computational methods to probe the protein-protein interactions involved in androgen receptor activation. The androgen receptor controls many of the processes that are associated with male sexual characteristics and is a potential target for prostate cancer treatment. 

Computer modelling of mutant miniproteins aids the discovery of novel androgen receptor inhibitors

Whilst the androgen receptor is activated by the hormones testosterone and dihydrotestosterone, its behaviour is modulated by proteins called coactivators. Brunsveld's team has studied how these coactivators bind to the receptor, with the eventual aim of finding new inhibitors. Knowing that a helical peptide sequence with an FXXLF motif (F = phenylalanine, L = leucine, X = unspecified) is key to protein binding to the receptor, the team looked at how variations in these peptides' structures - in particular their helix length - affect their binding affinity.

The researchers selected miniproteins with helices of differing lengths from the Protein Data Bank repository and modelled them computationally. They then substituted amino acids in each protein to introduce the FXXLF motif and simulated the binding of these mutants to the androgen receptor. In this way the team could identify candidate proteins, which they then synthesised and evaluated in experimental binding studies with the real receptor. 

The binding studies identified several miniproteins with micromolar binding affinities, making them comparable with one of the best peptide binders currently known for the androgen receptor. The team also discovered that miniproteins with helices comprising approximately 2 turns have the best binding affinities; and that longer helices give poorer binding due to charge/steric incompatibilities with the receptor.

Brunsveld says that by performing point mutations on their unoptimised protein sequences he hopes to obtain miniproteins with even stronger binding affinities. He stresses that while the miniproteins are unlikely to be suitable for use as therapeutics, 'what we try to learn with these miniproteins is the minimum motif that we need for binding to these receptors, so we can design small molecules based on these motifs.'

Kip Guy of St Jude Children's Research Hospital, Memphis, US, an expert in the fields of protein interactions and transcriptional activation complexes agrees. 'This work will have important implications for building better assays for detecting small molecule inhibitors,' he says. 'It could shed light on the specific details of the adaptation of [the ligand binding] site on the androgen receptor during binding that would allow much better design of inhibitors.' 

David Sharpe

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