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-Structure paper
タイトル | Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis. |
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ジャーナル・号・ページ | Nat Commun, Vol. 15, Issue 1, Page 3775, Year 2024 |
掲載日 | 2024年5月6日 |
著者 | Oliver J Acton / Devon Sheppard / Simone Kunzelmann / Sarah J Caswell / Andrea Nans / Ailidh J O Burgess / Geoff Kelly / Elizabeth R Morris / Peter B Rosenthal / Ian A Taylor / |
PubMed 要旨 | SAMHD1 regulates cellular nucleotide homeostasis, controlling dNTP levels by catalysing their hydrolysis into 2'-deoxynucleosides and triphosphate. In differentiated CD4+ macrophage and resting T- ...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. |
リンク | Nat Commun / PubMed:38710701 / PubMed Central |
手法 | EM (単粒子) |
解像度 | 2.65 - 3.43 Å |
構造データ | EMDB-18729, PDB-8qxj: EMDB-18730, PDB-8qxk: EMDB-18731, PDB-8qxl: EMDB-18732, PDB-8qxm: EMDB-18733, PDB-8qxn: EMDB-18734, PDB-8qxo: |
化合物 | ChemComp-DZ4: ChemComp-FE: ChemComp-MG: ChemComp-GTP: ChemComp-HOH: ChemComp-DCP: ChemComp-DTP: ChemComp-DCZ: ChemComp-3PO: |
由来 |
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キーワード | HYDROLASE / TRIPHOSPHOHYDROLASE / METALLO-ENZYME / BINUCLEAR / HD |