6TXF

Crystal structure of tetrameric human D137N-SAMHD1 (residues 109-626) with XTP, dAMPNPP and Mn

6TXF の概要

• エントリーDOI: 10.2210/pdb6txf/pdb
• 関連するPDBエントリー: 6TX0 6TXA 6TXC 6TXE
• 分子名称: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, FE (III) ION, MANGANESE (II) ION, ... (6 entities in total)
• 機能のキーワード: triphosphohydrolase, metallo-enzyme, binuclear, hd, hydrolase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 123866.07

構造登録者

Morris, E.R.,Kunzelmann, S.,Caswell, S.J.,Arnold, L.H.,Purkiss, A.G.,Kelly, G.,Taylor, I.A. (登録日: 2020-01-14, 公開日: 2020-06-24, 最終更新日: 2024-01-24)

主引用文献

Morris, E.R.,Caswell, S.J.,Kunzelmann, S.,Arnold, L.H.,Purkiss, A.G.,Kelly, G.,Taylor, I.A.
Crystal structures of SAMHD1 inhibitor complexes reveal the mechanism of water-mediated dNTP hydrolysis.
Nat Commun, 11:3165-3165, 2020

PubMed Abstract: SAMHD1 regulates cellular 2'-deoxynucleoside-5'-triphosphate (dNTP) homeostasis by catalysing the hydrolysis of dNTPs into 2'-deoxynucleosides and triphosphate. In CD4 myeloid lineage and resting T-cells, SAMHD1 blocks HIV-1 and other viral infections by depletion of the dNTP pool to a level that cannot support replication. SAMHD1 mutations are associated with the autoimmune disease Aicardi-Goutières syndrome and hypermutated cancers. Furthermore, SAMHD1 sensitises cancer cells to nucleoside-analogue anti-cancer therapies and is linked with DNA repair and suppression of the interferon response to cytosolic nucleic acids. Nevertheless, despite its requirement in these processes, the fundamental mechanism of SAMHD1-catalysed dNTP hydrolysis remained unknown. Here, we present structural and enzymological data showing that SAMHD1 utilises an active site, bi-metallic iron-magnesium centre that positions a hydroxide nucleophile in-line with the P-O bond to catalyse phosphoester bond hydrolysis. This precise molecular mechanism for SAMHD1 catalysis, reveals how SAMHD1 down-regulates cellular dNTP and modulates the efficacy of nucleoside-based anti-cancer and anti-viral therapies.

PubMed: 32576829
DOI: 10.1038/s41467-020-16983-2

実験手法

X-RAY DIFFRACTION (2.25 Å)