8QXJ

Cryo-EM structure of tetrameric human SAMHD1 with dApNHpp

8QXJ の概要

• エントリーDOI: 10.2210/pdb8qxj/pdb
• EMDBエントリー: 18729
• 分子名称: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, 2'-deoxy-5'-O-[(R)-hydroxy{[(R)-hydroxy(phosphonooxy)phosphoryl]amino}phosphoryl]adenosine, FE (III) 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: 4
• 化学式量合計: 295750.99

構造登録者

Acton, O.J.,Sheppard, D.,Rosenthal, P.B.,Taylor, I.A. (登録日: 2023-10-24, 公開日: 2024-05-15, 最終更新日: 2024-05-22)

主引用文献

Acton, O.J.,Sheppard, D.,Kunzelmann, S.,Caswell, S.J.,Nans, A.,Burgess, A.J.O.,Kelly, G.,Morris, E.R.,Rosenthal, P.B.,Taylor, I.A.
Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis.
Nat Commun, 15:3775-3775, 2024

PubMed Abstract: SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T-cells SAMHD1 activity results in the inhibition of HIV-1 infection through a dNTP blockade. In cancer, SAMHD1 desensitizes cells to nucleoside-analogue chemotherapies. Here we employ time-resolved cryogenic-EM imaging and single-particle analysis to visualise assembly, allostery and catalysis by this multi-subunit enzyme. Our observations reveal how dynamic conformational changes in the SAMHD1 quaternary structure drive the catalytic cycle. We capture five states at high-resolution in a live catalytic reaction, revealing how allosteric activators support assembly of a stable SAMHD1 tetrameric core and how catalysis is driven by the opening and closing of active sites through pairwise coupling of active sites and order-disorder transitions in regulatory domains. This direct visualisation of enzyme catalysis dynamics within an allostery-stabilised platform sets a precedent for mechanistic studies into the regulation of multi-subunit enzymes.

PubMed: 38710701
DOI: 10.1038/s41467-024-48237-w

実験手法

ELECTRON MICROSCOPY (2.65 Å)