7KG3

Crystal structure of CoV-2 Nsp3 Macrodomain

Summary for 7KG3

• Entry DOI: 10.2210/pdb7kg3/pdb
• Related: 7KFP 7KG0 7KG1 7KG6 7KG7 7KG8
• Descriptor: Non-structural protein 3, MALONATE ION, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (6 entities in total)
• Functional Keywords: hydrolase, sars-cov-2, macrodomain
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV)
• Total number of polymer chains: 1
• Total formula weight: 18894.27

Authors

Arvai, A.,Brosey, C.A.,Link, T.,Jones, D.E.,Ahmed, Z.,Tainer, J.A. (deposition date: 2020-10-15, release date: 2020-10-28, Last modification date: 2023-10-18)

Primary citation

Brosey, C.A.,Houl, J.H.,Katsonis, P.,Balapiti-Modarage, L.P.F.,Bommagani, S.,Arvai, A.,Moiani, D.,Bacolla, A.,Link, T.,Warden, L.S.,Lichtarge, O.,Jones, D.E.,Ahmed, Z.,Tainer, J.A.
Targeting SARS-CoV-2 Nsp3 macrodomain structure with insights from human poly(ADP-ribose) glycohydrolase (PARG) structures with inhibitors.
Prog.Biophys.Mol.Biol., 163:171-186, 2021

PubMed Abstract: Arrival of the novel SARS-CoV-2 has launched a worldwide effort to identify both pre-approved and novel therapeutics targeting the viral proteome, highlighting the urgent need for efficient drug discovery strategies. Even with effective vaccines, infection is possible, and at-risk populations would benefit from effective drug compounds that reduce the lethality and lasting damage of COVID-19 infection. The CoV-2 MacroD-like macrodomain (Mac1) is implicated in viral pathogenicity by disrupting host innate immunity through its mono (ADP-ribosyl) hydrolase activity, making it a prime target for antiviral therapy. We therefore solved the structure of CoV-2 Mac1 from non-structural protein 3 (Nsp3) and applied structural and sequence-based genetic tracing, including newly determined A. pompejana MacroD2 and GDAP2 amino acid sequences, to compare and contrast CoV-2 Mac1 with the functionally related human DNA-damage signaling factor poly (ADP-ribose) glycohydrolase (PARG). Previously, identified targetable features of the PARG active site allowed us to develop a pharmacologically useful PARG inhibitor (PARGi). Here, we developed a focused chemical library and determined 6 novel PARGi X-ray crystal structures for comparative analysis. We applied this knowledge to discovery of CoV-2 Mac1 inhibitors by combining computation and structural analysis to identify PARGi fragments with potential to bind the distal-ribose and adenosyl pockets of the CoV-2 Mac1 active site. Scaffold development of these PARGi fragments has yielded two novel compounds, PARG-345 and PARG-329, that crystallize within the Mac1 active site, providing critical structure-activity data and a pathway for inhibitor optimization. The reported structural findings demonstrate ways to harness our PARGi synthesis and characterization pipeline to develop CoV-2 Mac1 inhibitors targeting the ADP-ribose active site. Together, these structural and computational analyses reveal a path for accelerating development of antiviral therapeutics from pre-existing drug optimization pipelines.

PubMed: 33636189
DOI: 10.1016/j.pbiomolbio.2021.02.002

Experimental method

X-RAY DIFFRACTION (1.45 Å)