6U6Z

Human SAMHD1 bound to deoxyribo(TG*TTCA)-oligonucleotide

Summary for 6U6Z

• Entry DOI: 10.2210/pdb6u6z/pdb
• Descriptor: Deoxynucleoside triphosphate triphosphohydrolase SAMHD1, DNA polymer TG(PST)TCA, ZINC ION, ... (4 entities in total)
• Functional Keywords: samhd1, hiv, restriction factor, innate immunity, dntpase, deoxyribo-oligonucleotide, phosphorothioate, hydrolase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 254644.51

Authors

Taylor, A.B.,Yu, C.H.,Ivanov, D.N. (deposition date: 2019-08-30, release date: 2020-09-02, Last modification date: 2023-10-11)

Primary citation

Yu, C.H.,Bhattacharya, A.,Persaud, M.,Taylor, A.B.,Wang, Z.,Bulnes-Ramos, A.,Xu, J.,Selyutina, A.,Martinez-Lopez, A.,Cano, K.,Demeler, B.,Kim, B.,Hardies, S.C.,Diaz-Griffero, F.,Ivanov, D.N.
Nucleic acid binding by SAMHD1 contributes to the antiretroviral activity and is enhanced by the GpsN modification.
Nat Commun, 12:731-731, 2021

PubMed Abstract: SAMHD1 impedes infection of myeloid cells and resting T lymphocytes by retroviruses, and the enzymatic activity of the protein-dephosphorylation of deoxynucleotide triphosphates (dNTPs)-implicates enzymatic dNTP depletion in innate antiviral immunity. Here we show that the allosteric binding sites of the enzyme are plastic and can accommodate oligonucleotides in place of the allosteric activators, GTP and dNTP. SAMHD1 displays a preference for oligonucleotides containing phosphorothioate bonds in the Rp configuration located 3' to G nucleotides (GpsN), the modification pattern that occurs in a mechanism of antiviral defense in prokaryotes. In the presence of GTP and dNTPs, binding of GpsN-containing oligonucleotides promotes formation of a distinct tetramer with mixed occupancy of the allosteric sites. Mutations that impair formation of the mixed-occupancy complex abolish the antiretroviral activity of SAMHD1, but not its ability to deplete dNTPs. The findings link nucleic acid binding to the antiretroviral activity of SAMHD1, shed light on the immunomodulatory effects of synthetic phosphorothioated oligonucleotides and raise questions about the role of nucleic acid phosphorothioation in human innate immunity.

PubMed: 33531504
DOI: 10.1038/s41467-021-21023-8

Experimental method

X-RAY DIFFRACTION (2.1 Å)