9wrc: Difference between revisions

Latest revision as of 16:28, 25 September 2026

Crystal structure of ZER1 bound to MHGD degron

Structural highlights

9wrc is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3.22Å
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

ZER1_HUMAN Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC (PubMed:17304241, PubMed:31273098). Acts to target substrates bearing N-terminal degrons for proteasomal degradation with the first four residues of substrates being the key recognition elements (PubMed:33093214, PubMed:34214466, PubMed:36496439). Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation (PubMed:31273098).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2(ZER1) to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.

Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers.,Wang X, Jiang C, Zhao Y, Li R, Zhou Y, Yin S, Chen J, Yan S, Gu S, Li X, Yu Y, Gu Y, Dong C, Mi W Cell Rep. 2026 Jul 28;45(8):117740. doi: 10.1016/j.celrep.2026.117740. PMID:42519832^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Vasudevan S, Starostina NG, Kipreos ET. The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO Rep. 2007 Mar;8(3):279-86. Epub 2007 Feb 16. PMID:17304241 doi:https://dx.doi.org/7400895
↑ Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science. 2019 Jul 5;365(6448):eaaw4912. doi: 10.1126/science.aaw4912. PMID:31273098 doi:https://dx.doi.org/10.1126/science.aaw4912
↑ Robinson KS, Teo DET, Tan KS, Toh GA, Ong HH, Lim CK, Lay K, Au BV, Lew TS, Chu JJH, Chow VTK, Wang Y, Zhong FL, Reversade B. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science. 2020 Dec 4;370(6521):eaay2002. doi: 10.1126/science.aay2002. Epub 2020 , Oct 22. PMID:33093214 doi:https://dx.doi.org/10.1126/science.aay2002
↑ Yan X, Li Y, Wang G, Zhou Z, Song G, Feng Q, Zhao Y, Mi W, Ma Z, Dong C. Molecular basis for recognition of Gly/N-degrons by CRL2(ZYG11B) and CRL2(ZER1). Mol Cell. 2021 Aug 19;81(16):3262-3274.e3. PMID:34214466 doi:10.1016/j.molcel.2021.06.010
↑ Li Y, Zhao Y, Yan X, Ye C, Weirich S, Zhang B, Wang X, Song L, Jiang C, Jeltsch A, Dong C, Mi W. CRL2(ZER1/ZYG11B) recognizes small N-terminal residues for degradation. Nat Commun. 2022 Dec 10;13(1):7636. doi: 10.1038/s41467-022-35169-6. PMID:36496439 doi:https://dx.doi.org/10.1038/s41467-022-35169-6
↑ Wang X, Jiang C, Zhao Y, Li R, Zhou Y, Yin S, Chen J, Yan S, Gu S, Li X, Yu Y, Gu Y, Dong C, Mi W. Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers. Cell Rep. 2026 Jul 28;45(8):117740. doi: 10.1016/j.celrep.2026.117740. PMID:42519832 doi:https://dx.doi.org/10.1016/j.celrep.2026.117740

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OCA

[1] Vasudevan S, Starostina NG, Kipreos ET. The Caenorhabditis elegans cell-cycle regulator ZYG-11 defines a conserved family of CUL-2 complex components. EMBO Rep. 2007 Mar;8(3):279-86. Epub 2007 Feb 16. PMID:17304241 doi:https://dx.doi.org/7400895

[2] Timms RT, Zhang Z, Rhee DY, Harper JW, Koren I, Elledge SJ. A glycine-specific N-degron pathway mediates the quality control of protein N-myristoylation. Science. 2019 Jul 5;365(6448):eaaw4912. doi: 10.1126/science.aaw4912. PMID:31273098 doi:https://dx.doi.org/10.1126/science.aaw4912

[3] Robinson KS, Teo DET, Tan KS, Toh GA, Ong HH, Lim CK, Lay K, Au BV, Lew TS, Chu JJH, Chow VTK, Wang Y, Zhong FL, Reversade B. Enteroviral 3C protease activates the human NLRP1 inflammasome in airway epithelia. Science. 2020 Dec 4;370(6521):eaay2002. doi: 10.1126/science.aay2002. Epub 2020 , Oct 22. PMID:33093214 doi:https://dx.doi.org/10.1126/science.aay2002

[4] Yan X, Li Y, Wang G, Zhou Z, Song G, Feng Q, Zhao Y, Mi W, Ma Z, Dong C. Molecular basis for recognition of Gly/N-degrons by CRL2(ZYG11B) and CRL2(ZER1). Mol Cell. 2021 Aug 19;81(16):3262-3274.e3. PMID:34214466 doi:10.1016/j.molcel.2021.06.010

[5] Li Y, Zhao Y, Yan X, Ye C, Weirich S, Zhang B, Wang X, Song L, Jiang C, Jeltsch A, Dong C, Mi W. CRL2(ZER1/ZYG11B) recognizes small N-terminal residues for degradation. Nat Commun. 2022 Dec 10;13(1):7636. doi: 10.1038/s41467-022-35169-6. PMID:36496439 doi:https://dx.doi.org/10.1038/s41467-022-35169-6

[6] Wang X, Jiang C, Zhao Y, Li R, Zhou Y, Yin S, Chen J, Yan S, Gu S, Li X, Yu Y, Gu Y, Dong C, Mi W. Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers. Cell Rep. 2026 Jul 28;45(8):117740. doi: 10.1016/j.celrep.2026.117740. PMID:42519832 doi:https://dx.doi.org/10.1016/j.celrep.2026.117740

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[2]

[3]

[4]

[5]

[6]

@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 9wrc is ON HOLD  until 2027-09-11
+==Crystal structure of ZER1 bound to MHGD degron==
+<StructureSection load='9wrc' size='340' side='right'caption='[[9wrc]], [[Resolution|resolution]] 3.22&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[9wrc]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9WRC OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9WRC FirstGlance]. <br>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.22&#8491;</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=9wrc FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9wrc OCA], [https://pdbe.org/9wrc PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9wrc RCSB], [https://www.ebi.ac.uk/pdbsum/9wrc PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9wrc ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/ZER1_HUMAN ZER1_HUMAN] Serves as substrate adapter subunit in the E3 ubiquitin ligase complex ZYG11B-CUL2-Elongin BC (PubMed:17304241, PubMed:31273098). Acts to target substrates bearing N-terminal degrons for proteasomal degradation with the first four residues of substrates being the key recognition elements (PubMed:33093214, PubMed:34214466, PubMed:36496439). Involved in the clearance of proteolytic fragments generated by caspase cleavage during apoptosis since N-terminal glycine degrons are strongly enriched at caspase cleavage sites. Also important in the quality control of protein N-myristoylation in which N-terminal glycine degrons are conditionally exposed after a failure of N-myristoylation (PubMed:31273098).<ref>PMID:17304241</ref> <ref>PMID:31273098</ref> <ref>PMID:33093214</ref> <ref>PMID:34214466</ref> <ref>PMID:36496439</ref>
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Persistent infection with high-risk human papillomaviruses (HPVs), notably HPV-16 and HPV-18, underlies most cervical cancers and many head and neck cancers. Here, we report the structural and functional basis by which the viral oncoprotein E7 hijacks host CRL2(ZER1) to degrade retinoblastoma (Rb) protein and drive E2F-dependent proliferation. Crystal structures reveal that the N-terminal MH/N-degron of E7 engages a defined pocket within the armadillo (ARM)-repeat domain of ZER1. Disruption of this interface abolishes E7-ZER1 binding, prevents Rb degradation, silences E2F transcriptional programs, and impairs proliferation of HPV-positive cancer cells. Guided by these insights, we identify a first-in-class small-molecule inhibitor that blocks E7-ZER1 association, restores Rb stability, and selectively suppresses HPV-positive tumor growth in vivo. These results define a viral mimicry mechanism and nominate the ZER1 degron pocket as a ligandable therapeutic target for HPV-driven malignancies, highlighting translational opportunities for targeted therapy.
-Authors: Dong, C., Ma, J., Li, J.
+Molecular basis of the HPV E7-ZER1 axis reveals a ligandable vulnerability in HPV-positive cancers.,Wang X, Jiang C, Zhao Y, Li R, Zhou Y, Yin S, Chen J, Yan S, Gu S, Li X, Yu Y, Gu Y, Dong C, Mi W Cell Rep. 2026 Jul 28;45(8):117740. doi: 10.1016/j.celrep.2026.117740. PMID:42519832<ref>PMID:42519832</ref>
-Description: Crystal structure of ZER1 bound to MHGD degron
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
-[[Category: Li, J]]
+<div class="pdbe-citations 9wrc" style="background-color:#fffaf0;"></div>
-[[Category: Dong, C]]
+== References ==
-[[Category: Ma, J]]
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Homo sapiens]]
+[[Category: Large Structures]]
+[[Category: Dong C]]
+[[Category: Li J]]
+[[Category: Ma J]]

9wrc: Difference between revisions

Latest revision as of 16:28, 25 September 2026

Crystal structure of ZER1 bound to MHGD degron

Structural highlights

Function

Publication Abstract from PubMed

References

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