| Structural highlights
6cwy is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
| | Ligands: | FHJ, GOL, MG, SO4, ZN |
| Gene: | SAE1, AOS1, SUA1, UBLE1A (HUMAN), UBA2, SAE2, UBLE1B, HRIHFB2115 (HUMAN) |
| Resources: | FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT |
Function
[SAE1_HUMAN] The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.[1] [2] [3] [4] [5] [6] [7] [SAE2_HUMAN] The heterodimer acts as a E1 ligase for SUMO1, SUMO2, SUMO3, and probably SUMO4. It mediates ATP-dependent activation of SUMO proteins followed by formation of a thioester bond between a SUMO protein and a conserved active site cysteine residue on UBA2/SAE2.[8] [9] [10] [11] [12] [13]
Publication Abstract from PubMed
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 degrees 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.
Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme.,Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, Sessions EH, Divlianska DB, Davies C, Chen Y, Olsen SK Nat Commun. 2018 Dec 4;9(1):5145. doi: 10.1038/s41467-018-07015-1. PMID:30514846[14]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Okuma T, Honda R, Ichikawa G, Tsumagari N, Yasuda H. In vitro SUMO-1 modification requires two enzymatic steps, E1 and E2. Biochem Biophys Res Commun. 1999 Jan 27;254(3):693-8. PMID:9920803 doi:10.1006/bbrc.1998.9995
- ↑ Gong L, Li B, Millas S, Yeh ET. Molecular cloning and characterization of human AOS1 and UBA2, components of the sentrin-activating enzyme complex. FEBS Lett. 1999 Apr 1;448(1):185-9. PMID:10217437
- ↑ Desterro JM, Rodriguez MS, Kemp GD, Hay RT. Identification of the enzyme required for activation of the small ubiquitin-like protein SUMO-1. J Biol Chem. 1999 Apr 9;274(15):10618-24. PMID:10187858
- ↑ Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, Dasso M. Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J. 2001 Aug;15(10):1825-7. PMID:11481243
- ↑ Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001 Sep 21;276(38):35368-74. Epub 2001 Jul 12. PMID:11451954 doi:10.1074/jbc.M104214200
- ↑ Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J. 2005 Feb 9;24(3):439-51. Epub 2005 Jan 20. PMID:15660128
- ↑ Olsen SK, Capili AD, Lu X, Tan DS, Lima CD. Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature. 2010 Feb 18;463(7283):906-12. PMID:20164921 doi:10.1038/nature08765
- ↑ Azuma Y, Tan SH, Cavenagh MM, Ainsztein AM, Saitoh H, Dasso M. Expression and regulation of the mammalian SUMO-1 E1 enzyme. FASEB J. 2001 Aug;15(10):1825-7. PMID:11481243
- ↑ Tatham MH, Jaffray E, Vaughan OA, Desterro JM, Botting CH, Naismith JH, Hay RT. Polymeric chains of SUMO-2 and SUMO-3 are conjugated to protein substrates by SAE1/SAE2 and Ubc9. J Biol Chem. 2001 Sep 21;276(38):35368-74. Epub 2001 Jul 12. PMID:11451954 doi:10.1074/jbc.M104214200
- ↑ Wang J, Lee B, Cai S, Fukui L, Hu W, Chen Y. Conformational transition associated with E1-E2 interaction in small ubiquitin-like modifications. J Biol Chem. 2009 Jul 24;284(30):20340-8. doi: 10.1074/jbc.M109.000257. Epub 2009, May 14. PMID:19443651 doi:10.1074/jbc.M109.000257
- ↑ Lois LM, Lima CD. Structures of the SUMO E1 provide mechanistic insights into SUMO activation and E2 recruitment to E1. EMBO J. 2005 Feb 9;24(3):439-51. Epub 2005 Jan 20. PMID:15660128
- ↑ Wang J, Hu W, Cai S, Lee B, Song J, Chen Y. The intrinsic affinity between E2 and the Cys domain of E1 in ubiquitin-like modifications. Mol Cell. 2007 Jul 20;27(2):228-37. PMID:17643372 doi:https://dx.doi.org/10.1016/j.molcel.2007.05.023
- ↑ Olsen SK, Capili AD, Lu X, Tan DS, Lima CD. Active site remodelling accompanies thioester bond formation in the SUMO E1. Nature. 2010 Feb 18;463(7283):906-12. PMID:20164921 doi:10.1038/nature08765
- ↑ Lv Z, Yuan L, Atkison JH, Williams KM, Vega R, Sessions EH, Divlianska DB, Davies C, Chen Y, Olsen SK. Molecular mechanism of a covalent allosteric inhibitor of SUMO E1 activating enzyme. Nat Commun. 2018 Dec 4;9(1):5145. doi: 10.1038/s41467-018-07015-1. PMID:30514846 doi:https://dx.doi.org/10.1038/s41467-018-07015-1
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