6hoz

ADP-ribosylserine hydrolase ARH3 of Latimeria chalumnae in complex with inosine diphosphate ribose (IDPr)

spinqualitylabelsall models 6hoz, resolution 1.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6hoz is a 2 chain structure with sequence from Latimeria chalumnae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.77Å Ligands: ACT, GOL, MG, R5I, R7I Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function ADPRS_LATCH ADP-ribosylhydrolase that preferentially hydrolyzes the scissile alpha-O-linkage attached to the anomeric C1 position of ADP-ribose and acts on different substrates, such as proteins ADP-ribosylated on serine and threonine, free poly(ADP-ribose) and O-acetyl-ADP-D-ribose (PubMed:30472116). Specifically acts as a serine mono-ADP-ribosylhydrolase by mediating the removal of mono-ADP-ribose attached to serine residues on proteins, thereby playing a key role in DNA damage response (PubMed:30472116). Serine ADP-ribosylation of proteins constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (By similarity). Does not hydrolyze ADP-ribosyl-arginine, -cysteine, -diphthamide, or -asparagine bonds (By similarity). Also able to degrade protein free poly(ADP-ribose), which is synthesized in response to DNA damage: free poly(ADP-ribose) acts as a potent cell death signal and its degradation by ADPRHL2 protects cells from poly(ADP-ribose)-dependent cell death, a process named parthanatos (PubMed:30472116). Also hydrolyzes free poly(ADP-ribose) in mitochondria (By similarity). Specifically digests O-acetyl-ADP-D-ribose, a product of deacetylation reactions catalyzed by sirtuins (By similarity). Specifically degrades 1-O-acetyl-ADP-D-ribose isomer, rather than 2-O-acetyl-ADP-D-ribose or 3-O-acetyl-ADP-D-ribose isomers (By similarity).[UniProtKB:Q9NX46] Publication Abstract from PubMed Protein ADP-ribosylation is a highly dynamic post-translational modification. The rapid turnover is achieved, among others, by ADP-(ribosyl)hydrolases (ARHs), an ancient family of enzymes that reverses this modification. Recently ARHs came into focus due to their role as regulators of cellular stresses and tumor suppressors. Here we present a comprehensive structural analysis of the enzymatically active family members ARH1 and ARH3. These two enzymes have very distinct substrate requirements. Our data show that binding of the adenosine ribose moiety is highly diverged between the two enzymes, whereas the active sites harboring the distal ribose closely resemble each other. Despite this apparent similarity, we elucidate the structural basis for the selective inhibition of ARH3 by the ADP-ribose analogues ADP-HPD and arginine-ADP-ribose. Together, our biochemical and structural work provides important insights into the mode of enzyme-ligand interaction, helps to understand differences in their catalytic behavior, and provides useful tools for targeted drug design. (ADP-ribosyl)hydrolases: Structural Basis for Differential Substrate Recognition and Inhibition.,Rack JGM, Ariza A, Drown BS, Henfrey C, Bartlett E, Shirai T, Hergenrother PJ, Ahel I Cell Chem Biol. 2018 Nov 16. pii: S2451-9456(18)30389-1. doi:, 10.1016/j.chembiol.2018.11.001. PMID:30472116 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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