5AO2

Crystal structure of human SAMHD1 (amino acid residues 115-583) R164A variant bound to dGTP

5AO2 の概要

• エントリーDOI: 10.2210/pdb5ao2/pdb
• 関連するPDBエントリー: 5AO0 5AO1 5AO3 5AO4
• 分子名称: DEOXYNUCLEOSIDE TRIPHOSPHATE TRIPHOSPHOHYDROLASE SAMHD1, FE (III) ION, 2'-DEOXYGUANOSINE-5'-TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: hydrolase, deoxynucleoside triphosphate triphosphohydrolase, hiv restriction factor
• 由来する生物種: HOMO SAPIENS (HUMAN)
• 細胞内の位置: Nucleus : Q9Y3Z3
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 229444.06

構造登録者

Schwefel, D.,Taylor, I.A. (登録日: 2015-09-09, 公開日: 2015-10-14, 最終更新日: 2024-10-23)

主引用文献

Arnold, L.H.,Groom, H.C.T.,Kunzelmann, S.,Schwefel, D.,Caswell, S.J.,Ordonez, P.,Mann, M.C.,Rueschenbaum, S.,Goldstone, D.C.,Pennell, S.,Howell, S.A.,Stoye, J.P.,Webb, M.,Taylor, I.A.,Bishop, K.N.
Phospho-Dependent Regulation of Samhd1 Oligomerisation Couples Catalysis and Restriction.
Plos Pathog., 11:5194-, 2015

PubMed Abstract: SAMHD1 restricts HIV-1 infection of myeloid-lineage and resting CD4+ T-cells. Most likely this occurs through deoxynucleoside triphosphate triphosphohydrolase activity that reduces cellular dNTP to a level where reverse transcriptase cannot function, although alternative mechanisms have been proposed recently. Here, we present combined structural and virological data demonstrating that in addition to allosteric activation and triphosphohydrolase activity, restriction correlates with the capacity of SAMHD1 to form "long-lived" enzymatically competent tetramers. Tetramer disruption invariably abolishes restriction but has varied effects on in vitro triphosphohydrolase activity. SAMHD1 phosphorylation also ablates restriction and tetramer formation but without affecting triphosphohydrolase steady-state kinetics. However phospho-SAMHD1 is unable to catalyse dNTP turnover under conditions of nucleotide depletion. Based on our findings we propose a model for phosphorylation-dependent regulation of SAMHD1 activity where dephosphorylation switches housekeeping SAMHD1 found in cycling cells to a high-activity stable tetrameric form that depletes and maintains low levels of dNTPs in differentiated cells.

PubMed: 26431200
DOI: 10.1371/JOURNAL.PPAT.1005194

実験手法

X-RAY DIFFRACTION (2.966 Å)