Blog
About

0
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: not found
      • Article: not found

      Dual Labeling of the CBP/p300 KIX Domain for 19 F NMR Leads to Identification of a New Small-Molecule Binding Site

      Read this article at

      ScienceOpenPublisher
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Related collections

          Most cited references 33

          • Record: found
          • Abstract: found
          • Article: not found

          Anatomy of hot spots in protein interfaces.

          Binding of one protein to another is involved in nearly all biological functions, yet the principles governing the interaction of proteins are not fully understood. To analyze the contributions of individual amino acid residues in protein-protein binding we have compiled a database of 2325 alanine mutants for which the change in free energy of binding upon mutation to alanine has been measured (available at http://motorhead. ucsf.edu/thorn/hotspot). Our analysis shows that at the level of side-chains there is little correlation between buried surface area and free energy of binding. We find that the free energy of binding is not evenly distributed across interfaces; instead, there are hot spots of binding energy made up of a small subset of residues in the dimer interface. These hot spots are enriched in tryptophan, tyrosine and arginine, and are surrounded by energetically less important residues that most likely serve to occlude bulk solvent from the hot spot. Occlusion of solvent is found to be a necessary condition for highly energetic interactions. Copyright 1998 Academic Press.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Small-molecule inhibitors of protein-protein interactions: progressing toward the reality.

            The past 20 years have seen many advances in our understanding of protein-protein interactions (PPIs) and how to target them with small-molecule therapeutics. In 2004, we reviewed some early successes; since then, potent inhibitors have been developed for diverse protein complexes, and compounds are now in clinical trials for six targets. Surprisingly, many of these PPI clinical candidates have efficiency metrics typical of "lead-like" or "drug-like" molecules and are orally available. Successful discovery efforts have integrated multiple disciplines and make use of all the modern tools of target-based discovery-structure, computation, screening, and biomarkers. PPIs become progressively more challenging as the interfaces become more complex, i.e., as binding epitopes are displayed on primary, secondary, or tertiary structures. Here, we review the last 10 years of progress, focusing on the properties of PPI inhibitors that have advanced to clinical trials and prospects for the future of PPI drug discovery.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Biased signaling pathways in β2-adrenergic receptor characterized by 19F-NMR.

              Extracellular ligand binding to G protein-coupled receptors (GPCRs) modulates G protein and β-arrestin signaling by changing the conformational states of the cytoplasmic region of the receptor. Using site-specific (19)F-NMR (fluorine-19 nuclear magnetic resonance) labels in the β(2)-adrenergic receptor (β(2)AR) in complexes with various ligands, we observed that the cytoplasmic ends of helices VI and VII adopt two major conformational states. Changes in the NMR signals reveal that agonist binding primarily shifts the equilibrium toward the G protein-specific active state of helix VI. In contrast, β-arrestin-biased ligands predominantly impact the conformational states of helix VII. The selective effects of different ligands on the conformational equilibria involving helices VI and VII provide insights into the long-range structural plasticity of β(2)AR in partial and biased agonist signaling.
                Bookmark

                Author and article information

                Journal
                ChemBioChem
                ChemBioChem
                Wiley
                14394227
                May 04 2018
                May 04 2018
                April 06 2018
                : 19
                : 9
                : 963-969
                Affiliations
                [1 ]Department of Chemistry; University of Minnesota; 207 Pleasant Street, SE Minneapolis MN 55455 USA
                Article
                10.1002/cbic.201700686
                © 2018

                http://doi.wiley.com/10.1002/tdm_license_1.1

                http://onlinelibrary.wiley.com/termsAndConditions#am

                http://onlinelibrary.wiley.com/termsAndConditions#vor

                Comments

                Comment on this article