title: Conformational ensembles, signal transduction and residue hot spots: application to drug discovery.
abstract: A key step in drug development is the identification of both a protein target and its topological cellular network location and interactions, with regard to information flow in disease-causing events and to medication effects. Information flow involves a cascade of binding or covalent modification processes, with each step being affected by those that occur previously. Proteins are flexible, and information flows via dynamic changes in the distribution of conformational protein ensembles; molecular recognition is mainly determined by these changes. Drug discovery often focuses on signaling proteins situated at the crossroads of cellular networks; such signaling proteins have multiple partners that bind through shared binding sites. This review highlights these shared binding sites, and describes research to suggest that partners binding at these sites could at least partly interact via different energetically dominant 'hot-spot' residues. The data also indicate that, despite dynamic changes in the distribution of the conformational ensembles, the hot-spot conformations are retained in their pre-organized states.
authors.affiliation: Koc University, Center for Computational Biology and Bioinformatics, and College of Engineering, Rumelifeneri Yolu, 34450 Sariyer, Istanbul, Turkey.
authors.forename: Saliha Ece
authors.initials: SE
authors.lastname: Acuner Ozbabacan
authors.forename: Attila
authors.initials: A
authors.lastname: Gursoy
authors.forename: Ozlem
authors.initials: O
authors.lastname: Keskin
authors.forename: Ruth
authors.initials: R
authors.lastname: Nussinov
mesh_terms: D000495:Allosteric Site; D000818:Animals; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000378:metabolism; D055808:Drug Discovery / Q000379:methods*; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry* / Q000378:metabolism; D015398:Signal Transduction; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry / Q000378:metabolism; D018631:ras Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D008024:Ligands; D011506:Proteins; D054852:Small Molecule Libraries; D016159:Tumor Suppressor Protein p53; D018631:ras Proteins