9yuz

Structure of the human 20S proteasome in complex with a beta5-selective covalent syringolin analogue inhibitor.

spinqualitylabelsall models 9yuz, resolution 2.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9yuz is a 20 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.6Å Ligands: A1CY5 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA2_HUMAN The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. PSMA2 may have a potential regulatory effect on another component(s) of the proteasome complex through tyrosine phosphorylation. Publication Abstract from PubMed The syringolin natural products are covalent inhibitors of the 20S proteasome that inspire therapeutic development. Here, we report a new route to the syringolins amenable to solution and solid-phase synthesis that overcomes a problematic macrocyclization. Exploiting our synthetic approach and substrate mimicry models for proteasome inhibition by the syringolins, we generated a collection of hypothetically selective inhibitors of the Plasmodium falciparum proteasome, which is an emerging target for antimalarial drugs. We identified compounds from the library having high second-order rate constants for Plasmodium proteasome inhibition and nanomolar antiparasitic activity. They exhibited selectivity for the Plasmodium proteasome over the human proteasome. We solved cryo-EM structures of an inhibitor bound to both 20S proteasomes, revealing key contacts favoring species-selective inhibition. Together, this work provides an improved route to syringolin analogs, sheds new light on substrate mimicry by the syringolins, and provides a structural basis for the pursuit of new antimalarial drugs. An Optimized Route to the Syringolin Natural Products Enables Combinatorial Synthesis of Selective, Bioactive Inhibitors of the Plasmodium falciparum 20S Proteasome.,Gu X, Fajtova P, Yan NL, Saxena A, Fei F, Zhu J, Tse E, Melo A, Yoo E, Buchwald NH, Southworth DR, Bogyo M, Derisi JL, Gestwicki JE, O'Donoghue AJ, Sello JK J Med Chem. 2026 Apr 1. doi: 10.1021/acs.jmedchem.5c03223. PMID:41921688 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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