7l28

Crystal structure of the catalytic domain of human PDE3A bound to Trequinsin

spinqualitylabelsall models 7l28, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7l28 is a 4 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: X-ray diffraction, Resolution 2.2Å Ligands: ACT, MG, MN, XKG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Disease PDE3A_HUMAN Brachydactyly-arterial hypertension syndrome. The disease is caused by variants affecting the gene represented in this entry. Function PDE3A_HUMAN Cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.[UniProtKB:Q9Z0X4] Publication Abstract from PubMed DNMDP and related compounds, or velcrins, induce complex formation between the phosphodiesterase PDE3A and the SLFN12 protein, leading to a cytotoxic response in cancer cells that express elevated levels of both proteins. The mechanisms by which velcrins induce complex formation, and how the PDE3A-SLFN12 complex causes cancer cell death, are not fully understood. Here, we show that PDE3A and SLFN12 form a heterotetramer stabilized by binding of DNMDP. Interactions between the C-terminal alpha helix of SLFN12 and residues near the active site of PDE3A are required for complex formation, and are further stabilized by interactions between SLFN12 and DNMDP. Moreover, we demonstrate that SLFN12 is an RNase, that PDE3A binding increases SLFN12 RNase activity, and that SLFN12 RNase activity is required for DNMDP response. This new mechanistic understanding will facilitate development of velcrin compounds into new cancer therapies. Structure of PDE3A-SLFN12 complex reveals requirements for activation of SLFN12 RNase.,Garvie CW, Wu X, Papanastasiou M, Lee S, Fuller J, Schnitzler GR, Horner SW, Baker A, Zhang T, Mullahoo JP, Westlake L, Hoyt SH, Toetzl M, Ranaghan MJ, de Waal L, McGaunn J, Kaplan B, Piccioni F, Yang X, Lange M, Tersteegen A, Raymond D, Lewis TA, Carr SA, Cherniack AD, Lemke CT, Meyerson M, Greulich H Nat Commun. 2021 Jul 16;12(1):4375. doi: 10.1038/s41467-021-24495-w. PMID:34272366 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Phosphodiesterase 3D structures

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