PDBsum entry 4bzb

Hydrolase

PDB id: 4bzb

Contents

Protein chains

481 a.a.

Ligands

DGT ×12

Metals

_MG ×8

Waters ×877

References listed in PDB file

Key reference

• Title: Mechanism of allosteric activation of samhd1 by dgtp.
• Authors: X.Ji, Y.Wu, J.Yan, J.Mehrens, H.Yang, M.Delucia, C.Hao, A.M.Gronenborn, J.Skowronski, J.Ahn, Y.Xiong.
• Ref.: Nat Struct Biol, 2013, 20, 1304-1309. [DOI no: 10.1038/nsmb.2692]
• PubMed id: 24141705

Abstract

SAMHD1, a dNTP triphosphohydrolase (dNTPase), has a key role in human innate immunity. It inhibits infection of blood cells by retroviruses, including HIV, and prevents the development of the autoinflammatory Aicardi-Goutières syndrome (AGS). The inactive apo-SAMHD1 interconverts between monomers and dimers, and in the presence of dGTP the protein assembles into catalytically active tetramers. Here, we present the crystal structure of the human tetrameric SAMHD1-dGTP complex. The structure reveals an elegant allosteric mechanism of activation through dGTP-induced tetramerization of two inactive dimers. Binding of dGTP to four allosteric sites promotes tetramerization and induces a conformational change in the substrate-binding pocket to yield the catalytically active enzyme. Structure-based biochemical and cell-based biological assays confirmed the proposed mechanism. The SAMHD1 tetramer structure provides the basis for a mechanistic understanding of its function in HIV restriction and the pathogenesis of AGS.