Biomedical subjects

Roderick E Hubbard

Publications and source records attributed to Roderick E Hubbard.

4 recordsLinked to original sources

PubMed2003

Analysis and optimization of structure-based virtual screening protocols. (3). New methods and old problems in scoring function design.

Scoring function research remains a primary focus of current structure-based virtual screening (SVS) technology development. Here, we present an alternative method for scoring function design that attempts to combine crystallographic structural information with data derived from directly within SVS calculations. The technique utilizes a genetic algorithm (GA) to optimize functions based on binding property data derived from multiple virtual screening calculations. These calculations are undertaken on protein data bank (PDB) complex active sites using ligands of known binding mode in conjunction with "noise" compounds. The advantages of such an approach are that the function does not rely on assay data and that it can potentially use the "noise" binding data to recognize the sub-optimal docking interactions inherent in SVS calculations. Initial efforts in technique exploration using DOCK are presented, with comparisons made to existing DOCK scoring functions. An analysis of the problems inherent to scoring function development is also made, including issues in dataset creation and limitations in descriptor utility when viewed from the perspective of docking mode resolution. The future directions such studies might take are also discussed in detail.

Algorithms↗

PubMed2003

Making decisions for structural genomics.

A large number of structural genomics programmes have been established worldwide with the common aim of large-scale, high-throughput protein structure determination. Due to the considerable challenges posed by the experimental methods of structural determination (primarily X-ray crystallography and nuclear magnetic resonance spectroscopy) it is important to select and prioritise candidate molecules that will maximise the information gained from each new structure. This paper describes the scientific principles that underlie target selection and the various bioinformatics tools that may be employed in such selection procedures. Then follows a discussion of the availability of resources incorporating these methods and a description of the design and application of a purpose-built target selection resource for structural genomics.

Animals↗

PubMed2002

Interaction of transcriptional intermediary factor 2 nuclear receptor box peptides with the coactivator binding site of estrogen receptor alpha.

The activation function 2/ligand-dependent interaction between nuclear receptors and their coregulators is mediated by a short consensus motif, the so-called nuclear receptor (NR) box. Nuclear receptors exhibit distinct preferences for such motifs depending both on the bound ligand and on the NR box sequence. To better understand the structural basis of motif recognition, we characterized the interaction between estrogen receptor alpha and the NR box regions of the p160 coactivator TIF2. We have determined the crystal structures of complexes between the ligand-binding domain of estrogen receptor alpha and 12-mer peptides from the Box B2 and Box B3 regions of TIF2. Surprisingly, the Box B3 module displays an unexpected binding mode that is distinct from the canonical LXXLL interaction observed in other ligand-binding domain/NR box crystal structures. The peptide is shifted along the coactivator binding site in such a way that the interaction motif becomes LXXYL rather than the classical LXXLL. However, analysis of the binding properties of wild type NR box peptides, as well as mutant peptides designed to probe the Box B3 orientation, suggests that the Box B3 peptide primarily adopts the "classical" LXXLL orientation in solution. These results highlight the potential difficulties in interpretation of protein-protein interactions based on co-crystal structures using short peptide motifs.

Amino Acid Motifs↗

PubMed2002

Structure of a Cys25-->Ser mutant of human cathepsin S.

Cathepsin S (EC 3.4.22.27), a cysteine proteinase of the papain superfamily, plays a critical role in the generation of a major histocompatibility complex (MHC) class II restricted T-cell response by antigen-presenting cells. Therefore, selective inhibition of this enzyme may be useful in modulating class II restricted T-cell responses in immune-related disorders such as rheumatoid arthritis, multiple sclerosis and extrinsic asthma. The three-dimensional structure at 2.2 A resolution of the active-site Cys25-->Ser mutant presented here in an unliganded state provides further insight useful for the design of selective enzyme inhibitors.

Amino Acid Substitution↗