5thu

Crystal Structure of G304A HDAC8 in complex with M344

spinqualitylabelsall models 5thu, resolution 1.95Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5thu is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: B3N, GGG, K, ZN Related: 5ths, 5tht, 5thv Gene: HDAC8, HDACL1, CDA07 (HUMAN) Activity: Histone deacetylase, with EC number 3.5.1.98 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [HDAC8_HUMAN] Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. May play a role in smooth muscle cell contractility. Publication Abstract from PubMed Histone deacetylase 8 (HDAC8) catalyzes the hydrolysis of acetyl-l-lysine to yield products l-lysine and acetate through a mechanism in which a nucleophilic water molecule is activated by a histidine general base and a catalytic metal ion (Zn(2+) or Fe(2+)). Acetyl-l-lysine also requires activation by metal coordination and a hydrogen bond with catalytic tyrosine Y306, which also functions in transition state stabilization. Interestingly, Y306 is located in the conserved glycine-rich loop G(302)GGGY. The potential flexibility afforded by the tetraglycine segment may facilitate induced-fit conformational changes in Y306 between "in" and "out" positions, as observed in related deacetylases. To probe the catalytic importance of the glycine-rich loop in HDAC8, we rigidified this loop by preparing the G302A, G303A, G304A, and G305A mutants and measured their steady state kinetics and determined their X-ray crystal structures. Substantial losses of catalytic efficiency are observed (10-500-fold based on kcat/KM), particularly for G304A HDAC8 and G305A HDAC8. These mutants also exhibit the greatest structural changes for catalytic tyrosine Y306 (1.3-1.7 A shifts of the phenolic hydroxyl group). Molecular dynamics simulations further indicate that G304 and G305 undergo pronounced structural changes as residue 306 undergoes a transition between "in" and "out" conformations. Thus, the G304A and G305A substitutions likely compromise the position and conformational changes of Y306 required for substrate activation and transition state stabilization. The G302A and G303A substitutions have less severe catalytic consequences, and these substitutions may influence an internal channel through which product acetate is believed to exit. Structural and Functional Influence of the Glycine-Rich Loop G(302)GGGY on the Catalytic Tyrosine of Histone Deacetylase 8.,Porter NJ, Christianson NH, Decroos C, Christianson DW Biochemistry. 2016 Dec 6;55(48):6718-6729. doi: 10.1021/acs.biochem.6b01014. Epub, 2016 Nov 28. PMID:27933794 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Histone deacetylase 3D structures

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