PDBsum entry 4bzb

Hydrolase

PDB id: 4bzb

Contents

Protein chains

481 a.a.

Ligands

DGT ×12

Metals

_MG ×8

Waters ×877

PDB id:

4bzb

Name:

Hydrolase

Title:

Crystal structure of the tetrameric dgtp-bound samhd1 mutant catalytic core

Structure:

Deoxynucleoside triphosphate triphosphohydrolase samhd1. Chain: a, b, c, d. Fragment: hd domain, residues 113-626. Synonym: dntpase, dendritic cell-derived ifng-induced protein, dcip, monocyte protein 5, mop-5, sam domain and hd domain-containing protein 1, samhd1. Engineered: yes. Mutation: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 469008. Expression_system_variant: rosetta 2.

Resolution:

1.83Å R-factor: 0.190 R-free: 0.206

Authors:

X.Ji,H.Yang,Y.Wu,J.Yan,J.Mehrens,M.Delucia,C.Hao,A.M.Gronenborn, J.Skowronski,J.Ahn,Y.Xiong

Key ref:

X.Ji et al. (2013). Mechanism of allosteric activation of SAMHD1 by dGTP. Nat Struct Biol, 20, 1304-1309. PubMed id: 24141705 DOI: 10.1038/nsmb.2692

Date:

25-Jul-13 Release date: 23-Oct-13

Protein chains

Q9Y3Z3  (SAMH1_HUMAN) -  Deoxynucleoside triphosphate triphosphohydrolase SAMHD1 from Homo sapiens

Seq: 626 a.a.

Struc: 481 a.a.*

* PDB and UniProt seqs differ at 2 residue positions (black crosses)

Enzyme reactions

• Enzyme class: E.C.3.1.5.- - ?????

DOI no: 10.1038/nsmb.2692

Nat Struct Biol 20:1304-1309 (2013)

PubMed id: 24141705

Mechanism of allosteric activation of SAMHD1 by dGTP.

X.Ji, Y.Wu, J.Yan, J.Mehrens, H.Yang, M.DeLucia, C.Hao, A.M.Gronenborn, J.Skowronski, J.Ahn, Y.Xiong.

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.