@article{8ecf2ad890c8448fba40aa54dc6c0e78,
title = "ADP-ribose and analogues bound to the deMARylating macrodomain from the bat coronavirus HKU4",
abstract = "Macrodomains are proteins that recognize and hydrolyze ADP ribose (ADPR) modifications of intracellular proteins. Macrodomains are implicated in viral genome replication and interference with host cell immune responses. They are important to the infectious cycle of Coronaviridae and Togaviridae viruses. We describe crystal structures of the conserved macrodomain from the bat coronavirus (CoV) HKU4 in complex with ligands. The structures reveal a binding cavity that accommodates ADPR and analogs via local structural changes within the pocket. Using a radioactive assay, we present evidence of mono-ADPR (MAR) hydrolase activity. In silico analysis presents further evidence on recognition of the ADPR modification for hydrolysis. Mutational analysis of residues within the binding pocket resulted in diminished enzymatic activity and binding affinity. We conclude that the common structural features observed in the macrodomain in a bat CoV contribute to a conserved function that can be extended to other known macrodomains.",
keywords = "ADP-ribose, Coronavirus, Crystal structure, Macrodomain, Viral protein",
author = "Hammond, {Robert G.} and Norbert Schormann and McPherson, {Robert Lyle} and Leung, {Anthony K.L.} and Deivanayagam, {Champion C.S.} and Johnson, {Margaret A.}",
note = "Funding Information: ACKNOWLEDGMENTS. The work conducted in this study was supported by the NIH Grant R35GM119456, University of Alabama at Birmingham Faculty Startup Funding, and the University of Alabama at Birmingham Department of Chemistry. C.C.S.D. and N.S. are partially funded through R01DE029007. This work is based on research conducted at the Southeast Regional Collaborative Access Team 22-ID beamline, which is funded by the National Institute of General Medical Sciences from the NIH (P41 GM103403). The deMARylation assay was developed through NIH R01GM104135 (A.K.L.L.) and T32CA009110 (R.L.M.). This research used resources of the Advanced Photon Source. Use of the Advanced Photon Source is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number W-31-109-Eng-38. Portions of this work were excerpted from the following PhD thesis: Hammond, R., “Macrodomain mystery: investigating the structure-function link in novel Tylonycteris HKU4 and Rousettus HKU9 coronavirus proteins,” PhD thesis, University of Alabama at Birmingham, Birmingham, AL. Ann Arbor: ProQuest Dissertations and Theses, 2018 (87). Funding Information: The work conducted in this study was supported by the NIH Grant R35GM119456, University of Alabama at Birmingham Faculty Startup Funding, and the University of Alabama at Birmingham Department of Chemistry. C.C.S.D. and N.S. are partially funded through R01DE029007. This work is based on research conducted at the Southeast Regional Collaborative Access Team 22-ID beamline, which is funded by the National Institute of General Medical Sciences from the NIH (P41 GM103403). The deMARylation assay was developed through NIH R01GM104135 (A.K.L.L.) and T32CA009110 (R.L.M.). This research used resources of the Advanced Photon Source. Use of the Advanced Photon Source is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number W-31-109-Eng-38. Portions of this work were excerpted from the following PhD thesis: Hammond, R., “Macrodomain mystery: investigating the structure-function link in novel Tylonycteris HKU4 and Rousettus HKU9 coronavirus proteins,” PhD thesis, University of Alabama at Birmingham, Birmingham, AL. Ann Arbor: ProQuest Dissertations and Theses, 2018 (87). Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = jan,
day = "12",
doi = "10.1073/pnas.2004500118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "2",
}