The Experts below are selected from a list of 52614 Experts worldwide ranked by ideXlab platform

Zhixun Shen - One of the best experts on this subject based on the ideXlab platform.

Scott R Johnston - One of the best experts on this subject based on the ideXlab platform.

Hiroaki Suga - One of the best experts on this subject based on the ideXlab platform.

  • structural basis for potent inhibition of sirt2 deacetylase by a macrocyclic peptide inducing dynamic structural change
    Structure, 2014
    Co-Authors: Kenichiro Yamagata, Yuki Goto, Hiroshi Nishimasu, Jumpei Morimoto, Ryuichiro Ishitani, Naoshi Dohmae, Norihiko Takeda, Ryozo Nagai, Issei Komuro, Hiroaki Suga
    Abstract:

    SIRT2 deacetylates specific acetyllysine residues in diverse proteins and is implicated in a variety of cellular processes. SIRT2 inhibition thus has potentials to treat human diseases such as cancers and neurodegenerative disorders. We have recently developed a series of e-trifluoroacetyllysine-containing macrocyclic peptides, which inhibit the SIRT2 activity more potently than most other known inhibitors. Here, we report the crystal structure of human SIRT2 in complex with a macrocyclic peptide inhibitor, S2iL5, at 2.5 A resolution. The structure revealed that S2iL5 binds to the active site of SIRT2 through extensive interactions. A structural comparison of the SIRT2-S2iL5 complex with SIRT2 in the free form, and in complex with ADP-ribose, revealed that S2iL5 induces an open-to-Closed Domain movement and an unexpected helix-to-coil transition in a SIRT2-specific region. Our findings unveil the potential of macrocyclic peptides to bind target proteins by inducing dynamic structural changes.

Giuseppe Melacini - One of the best experts on this subject based on the ideXlab platform.

  • mechanism of selective enzyme inhibition through uncompetitive regulation of an allosteric agonist
    Journal of the American Chemical Society, 2018
    Co-Authors: Stephen Boulton, Rajeevan Selvaratnam, Jeanpaul Blondeau, Frank Lezoualch, Giuseppe Melacini
    Abstract:

    Classical uncompetitive inhibitors are potent pharmacological modulators of enzyme function. Since they selectively target enzyme-substrate complexes (E:S), their inhibitory potency is amplified by increasing substrate concentrations. Recently, an unconventional uncompetitive inhibitor, called CE3F4R, was discovered for the exchange protein activated by cAMP isoform 1 (EPAC1). Unlike conventional uncompetitive inhibitors, CE3F4R is uncompetitive with respect to an allosteric effector, cAMP, as opposed to the substrate (i.e., CE3F4R targets the E:cAMP rather than the E:S complex). However, the mechanism of CE3F4R as an uncompetitive inhibitor is currently unknown. Here, we elucidate the mechanism of CE3F4R's action using NMR spectroscopy. Due to limited solubility and line broadening, which pose major challenges for traditional structural determination approaches, we resorted to a combination of protein- and ligand-based NMR experiments to comparatively analyze EPAC mutations, inhibitor analogs, and cyclic nucleotide derivatives that trap EPAC at different stages of activation. We discovered that CE3F4R binds within the EPAC cAMP-binding Domain (CBD) at a subDomain interface distinct from the cAMP binding site, acting as a wedge that stabilizes a cAMP-bound mixed-intermediate. The mixed-intermediate includes attributes of both the apo/inactive and cAMP-bound/active states. In particular, the intermediate targeted by CE3F4R traps a CBD's hinge helix in its inactive conformation, locking EPAC into a Closed Domain topology that restricts substrate access to the catalytic Domain. The proposed mechanism of action also explains the isoform selectivity of CE3F4R in terms of a single EPAC1 versus EPAC2 amino acid difference that destabilizes the active conformation of the hinge helix.

  • Mechanism of Selective Enzyme Inhibition through Uncompetitive Regulation of an Allosteric Agonist
    2018
    Co-Authors: Stephen Boulton, Rajeevan Selvaratnam, Jeanpaul Blondeau, Frank Lezoualc’h, Giuseppe Melacini
    Abstract:

    Classical uncompetitive inhibitors are potent pharmacological modulators of enzyme function. Since they selectively target enzyme–substrate complexes (E:S), their inhibitory potency is amplified by increasing substrate concentrations. Recently, an unconventional uncompetitive inhibitor, called CE3F4R, was discovered for the exchange protein activated by cAMP isoform 1 (EPAC1). Unlike conventional uncompetitive inhibitors, CE3F4R is uncompetitive with respect to an allosteric effector, cAMP, as opposed to the substrate (i.e., CE3F4R targets the E:cAMP rather than the E:S complex). However, the mechanism of CE3F4R as an uncompetitive inhibitor is currently unknown. Here, we elucidate the mechanism of CE3F4R’s action using NMR spectroscopy. Due to limited solubility and line broadening, which pose major challenges for traditional structural determination approaches, we resorted to a combination of protein- and ligand-based NMR experiments to comparatively analyze EPAC mutations, inhibitor analogs, and cyclic nucleotide derivatives that trap EPAC at different stages of activation. We discovered that CE3F4R binds within the EPAC cAMP-binding Domain (CBD) at a subDomain interface distinct from the cAMP binding site, acting as a wedge that stabilizes a cAMP-bound mixed-intermediate. The mixed-intermediate includes attributes of both the apo/inactive and cAMP-bound/active states. In particular, the intermediate targeted by CE3F4R traps a CBD’s hinge helix in its inactive conformation, locking EPAC into a Closed Domain topology that restricts substrate access to the catalytic Domain. The proposed mechanism of action also explains the isoform selectivity of CE3F4R in terms of a single EPAC1 versus EPAC2 amino acid difference that destabilizes the active conformation of the hinge helix

Yanfeng Chen - One of the best experts on this subject based on the ideXlab platform.