A SARS-CoV-2-Human Protein-Protein Interaction Map Reveals Drug Targets and Potential Drug-Repurposing

David E. Gordon; Gwendolyn M. Jang; Mehdi Bouhaddou; Jiewei Xu; Kirsten Obernier; Matthew J O'Meara; Jeffrey Z. Guo; Danielle L. Swaney; Tia A. Tummino; Ruth Huttenhain; Robyn Kaake; Alicia L. Richards; Beril Tutuncuoglu; Helene Foussard; Jyoti Batra; Kelsey Haas; Maya Modak; Minkyu Kim; Paige Haas; Benjamin J. Polacco; Hannes Braberg; Jacqueline M. Fabius; Manon Eckhardt; Margaret Soucheray; Melanie Brewer; Merve Cakir; Michael J. McGregor; Qiongyu Li; Zun Zar Chi Naing; Yuan Zhou; Shiming Peng; Ilsa T. Kirby; James E. Melnyk; John S Chorba; Kevin Lou; Shizhong A. Dai; Wenqi Shen; Ying Shi; Ziyang Zhang; Inigo Barrio-Hernandez; Danish Memon; Claudia Hernandez-Armenta; Christopher J.P. Mathy; Tina Perica; Kala B. Pilla; Sai J. Ganesan; Daniel J. Saltzberg; Rakesh Ramachandran; Xi Liu; Sara B. Rosenthal; Lorenzo Calviello; Srivats Venkataramanan; Yizhu Lin; Stephanie A. Wankowicz; Markus Bohn; Phillip P. Sharp; Raphael Trenker; Janet M. Young; Devin A. Cavero; Joseph Hiatt; Theo Roth; Ujjwal Rathore; Advait Subramanian; Julia Noack; Mathieu Hubert; Ferdinand Roesch; Thomas Vallet; Björn Meyer; Kris M. White; Lisa Miorin; Oren S. Rosenberg; Kliment A. Verba; David Agard; Melanie Ott; Michael Emerman; Davide Ruggero; Adolfo Garcí-Sastre; Natalia Jura; Mark von Zastrow; Jack Taunton; Olivier Schwartz; Marco Vignuzzi; Christophe d'Enfert; Shaeri Mukherjee; Matt Jacobson; Harmit S. Malik; Danica G Fujimori; Trey Ideker; Charles S Craik; Stephen Floor; James S. Fraser; John Gross; Andrej Sali; Tanja Kortemme; Pedro Beltrao; Kevan Shokat; Brian K. Shoichet; Nevan J. Krogan

Orf6 peptide modeling. The proposed interaction between Orf6 and the NUP98-RAE1 complex was modeled in PyRosetta 4 103 (release v2020.02-dev61090) using the crystal structure of Vesicular stomatitis virus matrix (M) protein bound to NUP98-RAE1 as a template 66 (PDB 4OWR downloaded from the PDB-REDO server 104 ). The M protein chain (C) was truncated after residue 54 to restrict the model to the putative interaction motif in Orf6 (M protein residues 49-54, sequence DEMDTH). These residues were mutated to the Orf6 sequence, QPMEID, using the mutate_residue function in the module pyrosetta.toolbox, without repacking at this initial step. After all six residues were mutated, the full model was relaxed to a low energy conformation using the FastRelax protocol in the module pyrosetta.rosetta.protocols.relax. FastRelax was run with constraints to starting coordinates and scored with the ref2015 score function. The resulting model was inspected for any large . CC-BY 4.0 International license author/funder. It is made available under a The copyright holder for this preprint (which was not peer-reviewed) is the . https://doi.org/10.1101/2020.03.22.002386 doi: bioRxiv preprint energetic penalties associated with the modeled peptide residues or those NUP98 and RAE1 residues interacting with the peptide, and was found to have none. The model was visualized in PyMOL (The PyMOL Molecular Graphics System, Version 2.3.4 Schrödinger, LLC.). CUL2 ZYG11B homology model generation. The CRL2 ZYG11B homology model was built with Swissmodel 105 and Modeller 106 by using the homology template of each domain from PDB database (PDB codes: 4b8o, 5jh5,1g03, and 6r7n). The ZYG11B model has two structured domains: a leucine rich repeat (LRR) and Armadillo Repeat (ARM) at the N and C-terminus respectively. The linker between each domain was not modelled due to high flexibility between residues 32 to 49 and residues 304 to 322. Putative protein interaction surfaces on ZYG11B were modelled based on contiguous surface exposed residues that are conserved in ZYG11B orthologues from C. elegans to H. sapiens (ZY11B_HUMAN; ZY11B_MOUSE; F1M8P2_RAT; ZYG11_XENLA; ZYG11_DANRE; ZYG11_CAEEL) and located at typical substrate binding sites in the homologous structures of LRR and ARM domain co-complexes.