Analysis of HSP90-related folds with MED-SuMo classification approach

Three-dimensional structural information is critical for understanding functional protein properties and the precise mechanisms of protein functions implicated in physiological and pathological processes. Comparison and detection of protein binding sites are key steps for annotating structures with functional predictions and are extremely valuable steps in a drug design process. In this research area, MED-SuMo is a powerful technology to detect and characterize similar local regions on protein surfaces. Each amino acid residue’s potential chemical interactions are represented by specific surface chemical features (SCFs). The MED-SuMo heuristic is based on the representation of binding sites by a graph structure suitable for exploration by an efficient comparison algorithm. We use this approach to analyze one particular SCOP superfamily which includes HSP90 chaperone, MutL/DNA topoisomerase, histidine kinases, and α-ketoacid dehydrogenase kinase C (BCK). They share a common fold and a common region for ATP-binding. To analyze both similar and differing features of this fold, we use a novel classification method, the MED-SuMo multi approach (MED-SMA). We highlight common and distinct features of these proteins. The different clusters created by MED-SMA yield interesting observations. For instance, one cluster gathers three types of proteins (HSP90, topoisomerase VI, and BCK) which all bind the drug radicicol

Computational fragment-based drug design to explore the hydrophobic subpocket of the mitotic kinesin Eg5 allosteric binding site

International audienceEg5, a mitotic kinesin exclusively involved in the formation and function of the mitotic spindle has attracted interest as an anticancer drug target. Eg5 is co-crystallized with several inhibitors bound to its allosteric binding pocket. Each of these occupies a pocket formed by loop 5/helix alpha2 (L5/alpha2). Recently designed inhibitors additionally occupy a hydrophobic pocket of this site. The goal of the present study was to explore this hydrophobic pocket with our MED-SuMo fragment-based protocol, and thus discover novel chemical structures that might bind as inhibitors. The MED-SuMo software is able to compare and superimpose similar interaction surfaces upon the whole protein data bank (PDB). In a fragment-based protocol, MED-SuMo retrieves MED-Portions that encode protein-fragment binding sites and are derived from cross-mining protein-ligand structures with libraries of small molecules. Furthermore we have excluded intra-family MED-Portions derived from Eg5 ligands that occupy the hydrophobic pocket and predicted new potential ligands by hybridization that would fill simultaneously both pockets. Some of the latter having original scaffolds and substituents in the hydrophobic pocket are identified in libraries of synthetically accessible molecules by the MED-Search software

Functional annotation strategy for protein structures: Functional annotation strategy for protein structures

Whole-genome sequencing projects are a major source of unknown function proteins. However, as predicting protein function from sequence remains a difficult task, research groups recently started to use 3D protein structures and structural models to bypass it. MEDSuMo compares protein surfaces analyzing the composition and spatial distribution of specific chemical groups (hydrogen bond donor, acceptor, positive, negative, aromatic, hydrophobic, guanidinium, hydroxyl, acyl and glycine). It is able to recognize proteins that have similar binding sites and thus, may perform similar functions. We present here a fine example which points out the interest of MEDSuMo approach for functional structural annotation

A QSAR study confirming the heterogeneity of the HEPT derivatives series regarding their interaction with HIV reverse transcriptase

QSAR concerning the anti-HIV and cytotoxic activities of a series of HEPT analogues has been established using a Hansch-type approach (TSAR™), a neural network approach (TSAR) and a pharmacophore search method (CATALYST™). The techniques employed allowed reliable activity predictions and confirmed the heterogeneity of this series of compounds, which was previously established in biochemical experiments

Examples of MED-SuMo results for hypothetical protein () from (in green, PDB code : 2EWR, crystallized by the Joint Center for Structural Genomics, JCSG, )

<p><b>Copyright information:</b></p><p>Taken from "Functional annotation strategy for protein structures"</p><p></p><p>Bioinformation 2007;1(9):357-359.</p><p>Published online 19 Mar 2007</p><p>PMCID:PMC1891723.</p><p></p> (a) Complete superimposition of with the cell wall invertase inhibitor from (in blue, PDB code: 2CJ5), (b) local view of the residues superimposed by MED-SuMo, and the ligand acetate ion. (c) Superimposition of with rhizopuspepsin (in yellow, PDB code: 5APR), (d) with the statine ligand. (e) Superimposition of binding site of with Endothiapepsin (PDB code: 1OD1), the MEDSuMo groups are represented; blue: HBond donor, red: HBond acceptor, dark red: Positive, purple: hydroxyl function, light grey: hydrophobi