The mechanism of substrate-controlled allosteric regulation of SAMHD1 activated by GTP

Acta Crystallographica. Section D, Biological Crystallography
Chunfeng ZhuXiao-Fang Yu

Abstract

SAMHD1 is the only known eukaryotic deoxynucleoside triphosphate triphosphohydrolase (dNTPase) and is a major regulator of intracellular dNTP pools. It has been reported to be a potent inhibitor of retroviruses such as HIV-1 and endogenous retrotransposons. Previous crystal structures have revealed that SAMHD1 is activated by dGTP-dependent tetramer formation. However, recent data have indicated that the primary activator of SAMHD1 is GTP, not dGTP. Therefore, how its dNTPase activity is regulated needs to be further clarified. Here, five crystal structures of the catalytic core of SAMHD1 in complex with different combinations of GTP and dNTPs are reported, including a GTP-bound dimer and four GTP/dNTP-bound tetramers. The data show that human SAMHD1 contains two unique activator-binding sites in the allosteric pocket. The primary activator GTP binds to one site and the substrate dNTP (dATP, dCTP, dUTP or dTTP) occupies the other. Consequently, both GTP and dNTP are required for tetramer activation of the enzyme. In the absence of substrate binding, SAMHD1 adopts an inactive dimer conformation even when complexed with GTP. Furthermore, SAMHD1 activation is regulated by the concentration of dNTP. Thus, the level of dNTP pools is...Continue Reading

References

Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Jan 9, 2010·Acta Crystallographica. Section D, Biological Crystallography·Alexei Vagin, Alexei Teplyakov
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Garib N MurshudovAlexei A Vagin
Jun 14, 2012·Retrovirology·Alberto Brandariz-NuñezFelipe Diaz-Griffero
Aug 29, 2012·Nature Reviews. Microbiology·Diana AyindeOlivier Schwartz
Sep 14, 2012·Nature Medicine·Hanna-Mari BaldaufOliver T Keppler
Sep 14, 2012·Journal of Virology·Henning HofmannNathaniel R Landau
Oct 19, 2012·The Journal of Biological Chemistry·Gregory BergerAndrea Cimarelli
Oct 25, 2012·Retrovirology·Benjamin DescoursMonsef Benkirane
Feb 22, 2013·The Journal of Biological Chemistry·Junpeng YanJacek Skowronski
Jul 5, 2013·PLoS Pathogens·Joseph A HollenbaughBaek Kim
Jul 17, 2013·Proceedings of the National Academy of Sciences of the United States of America·Elisa FranzolinVera Bianchi
Jul 25, 2013·The Journal of Biological Chemistry·Sarah M AmieBaek Kim
Aug 22, 2013·The EMBO Journal·Ferdinand Roesch, Olivier Schwartz
Sep 27, 2013·Journal of Virology·Eui Tae KimMatthew D Weitzman
Oct 22, 2013·Nature Structural & Molecular Biology·Xiaoyun JiYong Xiong
Apr 23, 2014·Proceedings of the National Academy of Sciences of the United States of America·Erik C HansenJames T Stivers
Oct 1, 2014·Proceedings of the National Academy of Sciences of the United States of America·Xiaoyun JiYong Xiong
Jan 1, 1997·Methods in Enzymology·Zbyszek Otwinowski, Wladek Minor

❮ Previous
Next ❯

Citations

Nov 29, 2015·Cancer Chemotherapy and Pharmacology·Chiara RampazzoLars Petter Jordheim
Apr 27, 2017·Reviews in Medical Virology·Miaomiao LiJun Li
Apr 12, 2017·Antioxidants & Redox Signaling·Christopher H MauneyThomas Hollis
Jul 13, 2019·Biochemical Society Transactions·Elizabeth R Morris, Ian A Taylor
Feb 23, 2020·The Journal of Biological Chemistry·Chu WangXianghui Yu
Mar 28, 2018·Autoimmunity·Christopher H Mauney, Thomas Hollis
Mar 3, 2017·Journal of Computer-aided Molecular Design·Francesca CardamoneAlessandro Desideri
Mar 30, 2018·Journal of Computer-aided Molecular Design·Francesca CardamoneAlessandro Desideri
Dec 7, 2016·The Journal of Biological Chemistry·Nicolin BlochNathaniel R Landau
Apr 5, 2020·Viruses·Si'Ana A CogginsBaek Kim
Oct 12, 2018·Proceedings of the National Academy of Sciences of the United States of America·Kirsten M KnechtYong Xiong
Jan 29, 2021·The Journal of Biological Chemistry·Chu WangXianghui Yu
Apr 4, 2021·Viruses·Janina Deutschmann, Thomas Gramberg
Nov 3, 2020·Journal of Chemical Information and Modeling·Gauri ThapaSwati Bhattacharya
Sep 29, 2017·Journal of Chemical Information and Modeling·Kajwal Kumar PatraSwati Bhattacharya

❮ Previous
Next ❯

Related Concepts

Trending Feeds

COVID-19

Coronaviruses encompass a large family of viruses that cause the common cold as well as more serious diseases, such as the ongoing outbreak of coronavirus disease 2019 (COVID-19; formally known as 2019-nCoV). Coronaviruses can spread from animals to humans; symptoms include fever, cough, shortness of breath, and breathing difficulties; in more severe cases, infection can lead to death. This feed covers recent research on COVID-19.

Blastomycosis

Blastomycosis fungal infections spread through inhaling Blastomyces dermatitidis spores. Discover the latest research on blastomycosis fungal infections here.

Nuclear Pore Complex in ALS/FTD

Alterations in nucleocytoplasmic transport, controlled by the nuclear pore complex, may be involved in the pathomechanism underlying multiple neurodegenerative diseases including Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. Here is the latest research on the nuclear pore complex in ALS and FTD.

Applications of Molecular Barcoding

The concept of molecular barcoding is that each original DNA or RNA molecule is attached to a unique sequence barcode. Sequence reads having different barcodes represent different original molecules, while sequence reads having the same barcode are results of PCR duplication from one original molecule. Discover the latest research on molecular barcoding here.

Chronic Fatigue Syndrome

Chronic fatigue syndrome is a disease characterized by unexplained disabling fatigue; the pathology of which is incompletely understood. Discover the latest research on chronic fatigue syndrome here.

Evolution of Pluripotency

Pluripotency refers to the ability of a cell to develop into three primary germ cell layers of the embryo. This feed focuses on the mechanisms that underlie the evolution of pluripotency. Here is the latest research.

Position Effect Variegation

Position Effect Variagation occurs when a gene is inactivated due to its positioning near heterochromatic regions within a chromosome. Discover the latest research on Position Effect Variagation here.

STING Receptor Agonists

Stimulator of IFN genes (STING) are a group of transmembrane proteins that are involved in the induction of type I interferon that is important in the innate immune response. The stimulation of STING has been an active area of research in the treatment of cancer and infectious diseases. Here is the latest research on STING receptor agonists.

Microbicide

Microbicides are products that can be applied to vaginal or rectal mucosal surfaces with the goal of preventing, or at least significantly reducing, the transmission of sexually transmitted infections. Here is the latest research on microbicides.