Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme

Lv, Zongyang; Yuan, Lingmin; Atkison, James H.; Williams, Katelyn M.; Vega, Ramir; Sessions, E. Hampton; Divlianska, Daniela B.; Davies, Christopher; Chen, Yuan; Olsen, Shaun K.

doi:10.1038/s41467-018-07015-1

Title: Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme

Journal Article · 03 December 2018 · Nature Communications

DOI: https://doi.org/10.1038/s41467-018-07015-1 · OSTI ID:1485676

Lv, Zongyang ^[1]; Yuan, Lingmin ^[2]; Atkison, James H. ^[2]; Williams, Katelyn M. ^[2]; Vega, Ramir ^[3]; Sessions, E. Hampton ^[4]; Divlianska, Daniela B. ^[4]; Davies, Christopher ^[2]; Chen, Yuan ^[3];

^[2]

Medical Univ. of South Carolina, Charleston, SC (United States); DOE/OSTI
Medical Univ. of South Carolina, Charleston, SC (United States)
Beckman Research Inst. of City of Hope, Duarte, CA (United States)
Sanford Burnham Prebys Medical Discovery Inst. at Lake Nona, Orlando, FL (United States)

E1 enzymes activate ubiquitin (Ub) and ubiquitin-like modifiers (Ubls) in the first step of Ub/Ubl conjugation cascades and represent potential targets for therapeutic intervention in cancer and other life-threatening diseases. Here, we report the crystal structure of the E1 enzyme for the Ubl SUMO in complex with a recently discovered and highly specific covalent allosteric inhibitor (COH000). The structure reveals that COH000 targets a cryptic pocket distinct from the active site that is completely buried in all previous SUMO E1 structures and that COH000 binding to SUMO E1 is accompanied by a network of structural changes that altogether lock the enzyme in a previously unobserved inactive conformation. These structural changes include disassembly of the active site and a 180° rotation of the catalytic cysteine-containing SCCH domain, relative to conformational snapshots of SUMO E1 poised to catalyze adenylation. Altogether, our study provides a molecular basis for the inhibitory mechanism of COH000 and its SUMO E1 specificity, and also establishes a framework for potential development of molecules targeting E1 enzymes for other Ubls at a cryptic allosteric site.

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Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)

Sponsoring Organization:: NIH; USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1485676

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 9; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Kerriamycin B inhibits protein SUMOylation Fukuda, Isao; Ito, Akihiro; Uramoto, Masakazu The Journal of Antibiotics, Vol. 62, Issue 4 https://doi.org/10.1038/ja.2009.10	journal	March 2009
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Active site remodelling accompanies thioester bond formation in the SUMO E1 Olsen, Shaun K.; Capili, Allan D.; Lu, Xuequan Nature, Vol. 463, Issue 7283 https://doi.org/10.1038/nature08765	journal	February 2010
Probing the roles of SUMOylation in cancer cell biology by using a selective SAE inhibitor He, Xingyue; Riceberg, Jessica; Soucy, Teresa Nature Chemical Biology, Vol. 13, Issue 11 https://doi.org/10.1038/nchembio.2463	journal	September 2017
A small-molecule inhibitor of the ubiquitin activating enzyme for cancer treatment Hyer, Marc L.; Milhollen, Michael A.; Ciavarri, Jeff Nature Medicine, Vol. 24, Issue 2 https://doi.org/10.1038/nm.4474	journal	January 2018
Ubiquitin-like protein activation by E1 enzymes: the apex for downstream signalling pathways Schulman, Brenda A.; Wade Harper, J. Nature Reviews Molecular Cell Biology, Vol. 10, Issue 5 https://doi.org/10.1038/nrm2673	journal	April 2009
Structural insights into the mechanism and E2 specificity of the RBR E3 ubiquitin ligase HHARI Yuan, Lingmin; Lv, Zongyang; Atkison, James H. Nature Communications, Vol. 8, Issue 1 https://doi.org/10.1038/s41467-017-00272-6	journal	August 2017
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The ubiquitin-like protein Smt3p is activated for conjugation to other proteins by an Aos1p/Uba2p heterodimer Johnson, E. S. The EMBO Journal, Vol. 16, Issue 18 https://doi.org/10.1093/emboj/16.18.5509	journal	September 1997
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Coot model-building tools for molecular graphics Emsley, Paul; Cowtan, Kevin Acta Crystallographica Section D Biological Crystallography, Vol. 60, Issue 12, p. 2126-2132 https://doi.org/10.1107/S0907444904019158	journal	November 2004
MolProbity : all-atom structure validation for macromolecular crystallography Chen, Vincent B.; Arendall, W. Bryan; Headd, Jeffrey J. Acta Crystallographica Section D Biological Crystallography, Vol. 66, Issue 1 https://doi.org/10.1107/S0907444909042073	journal	December 2009
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SUMO Modification of Huntingtin and Huntington's Disease Pathology Steffan, J. S. Science, Vol. 304, Issue 5667 https://doi.org/10.1126/science.1092194	journal	April 2004
Rhes, a Striatal Specific Protein, Mediates Mutant-Huntingtin Cytotoxicity Subramaniam, S.; Sixt, K. M.; Barrow, R. Science, Vol. 324, Issue 5932 https://doi.org/10.1126/science.1172871	journal	June 2009
A SUMOylation-Dependent Transcriptional Subprogram Is Required for Myc-Driven Tumorigenesis Kessler, J. D.; Kahle, K. T.; Sun, T. Science, Vol. 335, Issue 6066 https://doi.org/10.1126/science.1212728	journal	December 2011
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Sumoylation: A Regulatory Protein Modification in Health and Disease Flotho, Annette; Melchior, Frauke Annual Review of Biochemistry, Vol. 82, Issue 1 https://doi.org/10.1146/annurev-biochem-061909-093311	journal	June 2013
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Modification of Proteins by Ubiquitin and Ubiquitin-Like Proteins Kerscher, Oliver; Felberbaum, Rachael; Hochstrasser, Mark Annual Review of Cell and Developmental Biology, Vol. 22, Issue 1 https://doi.org/10.1146/annurev.cellbio.22.010605.093503	journal	November 2006
Crystal Structure of UBA2ufd-Ubc9: Insights into E1-E2 Interactions in Sumo Pathways Wang, Jing; Taherbhoy, Asad M.; Hunt, Harold W. PLoS ONE, Vol. 5, Issue 12 https://doi.org/10.1371/journal.pone.0015805	journal	December 2010
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A gene-expression screen identifies a non-toxic sumoylation inhibitor that mimics SUMO-less human LRH-1 in liver Suzawa, Miyuki; Miranda, Diego A.; Ramos, Karmela A. eLife, Vol. 4 https://doi.org/10.7554/eLife.09003	journal	December 2015

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Structural basis for adenylation and thioester bond formation in the ubiquitin E1 Hann, Zachary S.; Ji, Cheng; Olsen, Shaun K. Proceedings of the National Academy of Sciences, Vol. 116, Issue 31 https://doi.org/10.1073/pnas.1905488116	journal	June 2019
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59 BASIC BIOLOGICAL SCIENCES
Enzyme mechanisms
Neddylation
Sumoylation
Ubiquitylation
X-ray crystallography

Title: Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme

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