Recognizing Protein-Ligand Binding Sites by Global Structural Alignment and Local Geometry Refinement
STRUCTURE
Authors: Roy, Ambrish; Zhang, Yang
Abstract
Proteins perform functions through interacting with other molecules. However, structural details for most of the protein-ligand interactions are unknown. We present a comparative approach (COFACTOR) to recognize functional sites of protein-ligand interactions using low-resolution protein structural models, based on a global-to-local sequence and structural comparison algorithm. COFACTOR was tested on 501 proteins, which harbor 582 natural and drug-like ligand molecules. Starting from I-TASSER structure predictions, the method successfully identifies ligand-binding pocket locations for 65% of apo receptors with an average distance error 2 angstrom. The average precision of binding-residue assignments is 46% and 137% higher than that by FINDSITE and ConCavity. In CASP9, COFACTOR achieved a binding-site prediction precision 72% and Matthews correlation coefficient 0.69 for 31 blind test proteins, which was significantly higher than all other participating methods. These data demonstrate the power of structure-based approaches to protein-ligand interaction predictions applicable for genome-wide structural and functional annotations.
The association of taxane resistance genes with the clinical course of ovarian carcinoma
GENOMICS
Authors: Ehrlichova, Marie; Mohelnikova-Duchonova, Beatrice; Hrdy, Jiri; Brynychova, Veronika; Mrhalova, Marcela; Kodet, Roman; Rob, Lukas; Pluta, Marek; Gut, Ivan; Soucek, Pavel; Vaclavikova, Radka
Abstract
Taxane and platinum-based chemotherapy regimens are standard treatment for advanced ovarian carcinoma. Expression levels of putative markers of taxane resistance in carcinoma tissues and paired peritoneal samples (n = 55) and in 16 samples of ovaries without signs of carcinoma were compared with clinical data and the patients' time to progression. KIF14, PRC1, CIT and ABCC1 genes were significantly overexpressed in carcinomas when compared with normal ovarian tissues, while ABCB1 and CASP9 expression was decreased. Associations of protein expression of the proliferation marker Ki-67 with KIF14, PRC1, ABCB1 and CASP2 were found. Lastly, it was discovered that ABCB1 and CASP2 levels associated with FIGO stage and that the CIT level associated with the time to progression of ovarian carcinoma patients (P < 0.0001). In conclusion, ABCB1, CASP2, KIF14, PRC1 and CIT genes seem to associate with surrogate markers of ovarian carcinoma progression and CIT gene associates with therapy outcome. (C) 2013 Elsevier Inc. All rights reserved.