4BZC

Crystal structure of the tetrameric dGTP-bound wild type SAMHD1 catalytic core

Summary for 4BZC

• Entry DOI: 10.2210/pdb4bzc/pdb
• Related: 4BZB
• Descriptor: DEOXYNUCLEOSIDE TRIPHOSPHATE TRIPHOSPHOHYDROLASE SAMHD1, 2'-deoxyguanosine-5'-O-(1-thiotriphosphate), MANGANESE (II) ION, ... (5 entities in total)
• Functional Keywords: hydrolase, hiv restriction factor, dntpase
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus: Q9Y3Z3
• Total number of polymer chains: 4
• Total formula weight: 260229.22

Authors

Ji, X.,Yang, H.,Wu, Y.,Yan, J.,Mehrens, J.,DeLucia, M.,Hao, C.,Gronenborn, A.M.,Skowronski, J.,Ahn, J.,Xiong, Y. (deposition date: 2013-07-25, release date: 2013-10-23, Last modification date: 2023-12-20)

Primary citation

Ji, X.,Wu, Y.,Yan, J.,Mehrens, J.,Yang, H.,Delucia, M.,Hao, C.,Gronenborn, A.M.,Skowronski, J.,Ahn, J.,Xiong, Y.
Mechanism of Allosteric Activation of Samhd1 by Dgtp
Nat.Struct.Mol.Biol., 20:1304-, 2013

PubMed 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.

PubMed: 24141705
DOI: 10.1038/NSMB.2692

Experimental method

X-RAY DIFFRACTION (2.88 Å)