No abstract

The tumour suppressor p53 is the most frequently mutated gene in human cancer. Reactivation of mutant p53 by small molecules is an exciting potential cancer therapy. Although several compounds restore wild-type function to mutant p53, their binding sites and mechanisms of action are elusive. Here computational methods identify a transiently open binding pocket between loop L1 and sheet S3 of the p53 core domain. Mutation of residue Cys124, located at the centre of the pocket, abolishes p53 reactivation of mutant R175H by PRIMA-1, a known reactivation compound. Ensemble-based virtual screening against this newly revealed pocket selects stictic acid as a potential p53 reactivation compound. In human osteosarcoma cells, stictic acid exhibits dose-dependent reactivation of p21 expression for mutant R175H more strongly than does PRIMA-1. These results indicate the L1/S3 pocket as a target for pharmaceutical reactivation of p53 mutants.

The geographic diffusion of highly pathogenic influenza A H5N1 has largely been traced from the perspective of the virus's victims. Birds of a variety of avian orders have been sampled across localities, and their infection has been identified by a general genetic test. Another approach tracks the migration from the perspective of the virus alone, by way of a phylogeography of H5N1 genetic sequences. Although several phylogenies in the literature have labeled H5N1 clades by geographic region, none has analytically inferred the history of the virus's migration. With a statistical phylogeography of 192 hemagglutinin and neuraminidase isolates, we show that the Chinese province of Guangdong is the source of multiple H5N1 strains spreading at both regional and international scales. In contrast, Indochina appears to be a regional sink, at the same time demonstrating bidirectional dispersal among localities within the region. An evolutionary trace of HA 1 across the phylogeography suggests a mechanism by which H5N1 is able to infect repeated cycles of host species across localities, regardless of the host species first infected in each locale. The trace also hypothesizes amino acid replacements that preceded the first recorded outbreak of pathogenic H5N1 in Hong Kong, 1997.phylogeny ͉ geography ͉ epidemiology ͉ parallelism ͉ diffusion

In recent protein structure prediction research there has been a great deal of interest in using amino acid interaction preferences (e.g. contact potentials or potentials of mean force) to align ('thread') a protein sequence to a known structural motif. An important open question is whether a polynomial time algorithm for finding the globally optimal threading is possible. We identify the two critical conditions governing this question: (i) variable-length gaps are admitted into the alignment, and (il) interactions between amino acids from the sequence are admitted into the score function. We prove that if both these conditions are allowed then the protein threading decision problem (does there exist a threading with a score ^K?) is NP-complete (in the strong sense, i.e. is not merely a number problem) and the related problem of finding the globally optimal protein threading is NP-hard. Therefore, no polynomial time algorithm is possible (unless P = NP). This result augments existing proofs that the direct protein folding problem is NP-complete by providing the corresponding proof for the 'inverse' protein folding problem. It provides a theoretical basis for understanding algorithms currently in use and indicates that computational strategies from other NPcomplete problems may be useful for predictive algorithms.