IF 5.7 2区生物学

Structure Pub Date : 2025-10-03 DOI: 10.1016/j.str.2025.09.006

Evan J. McMahon, Alexander G. Cioffi, Patrick R. Visperas, Yueqing Lin, Michael Shaghafi, Courtney M. Daczkowski, Johannes C. Hermann, Robert A. Everley, Richard M. Neve, Daniel A. Erlanson, Kevin R. Webster, Vikram Narayan, Weiru Wang

{"title":"Structural basis for DCAF2 as a novel E3 ligase for PROTAC-mediated targeted protein degradation","authors":"Evan J. McMahon, Alexander G. Cioffi, Patrick R. Visperas, Yueqing Lin, Michael Shaghafi, Courtney M. Daczkowski, Johannes C. Hermann, Robert A. Everley, Richard M. Neve, Daniel A. Erlanson, Kevin R. Webster, Vikram Narayan, Weiru Wang","doi":"10.1016/j.str.2025.09.006","DOIUrl":"https://doi.org/10.1016/j.str.2025.09.006","url":null,"abstract":"Targeted protein degradation (TPD) leverages the ubiquitin-proteasome system to eliminate disease-causing proteins via E3 ligases. To date, the field is limited to utilizing a few of the over 600 human E3 ligases. To expand this repertoire, we conducted structural and functional validation of DDB1 (Damage-specific DNA binding protein 1) and Cullin-associated factor (DCAF)2 (DTL/CDT2), a Cullin4-RING ligase substrate adaptor implicated in DNA damage response and cancer, as a novel E3 for TPD. Cryoelectron microscopy (cryo-EM) structures of the DCAF2:DDB1:DDA1 complex (3.3 Å), a ligand bound complex (3.1 Å), and a ternary complex with a covalent proteolysis-targeting chimera (PROTAC) and BRD4 (3.4 Å) reveal PROTAC-mediated substrate recruitment. Using covalent bifunctional tool compounds engaging residue C141 in the WD40 domain, we demonstrate robust ubiquitination in biochemical assays and cellular TPD using the COFFEE (covalent functionalization followed by E3 electroporation) method. These findings position DCAF2 as a promising E3 adaptor for PROTAC strategies and identify C141 as a relevant site for future PROTAC discovery.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"52 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145209661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Allosteric regulation of fungal fatty acid synthesis 真菌脂肪酸合成的变构调节

IF 5.7 2区生物学

Structure Pub Date : 2025-10-02 DOI: 10.1016/j.str.2025.09.005

S. M. Naimul Hasan, Elnaz Khalili Samani, Alexander F.A. Keszei, Mahtab Heydari, Mohammad T. Mazhab-Jafari

引用次数: 0

Toward a thermodynamic taxonomy of amyloid fibrils 淀粉样原纤维的热力学分类

IF 5.7 2区生物学

Structure Pub Date : 2025-10-02 DOI: 10.1016/j.str.2025.08.010

Nikolaos Louros, Joost Schymkowitz, Frederic Rousseau

引用次数: 0

A triple take on antigen receptor recognition of PE PE抗原受体识别的三重研究

IF 5.7 2区生物学

Structure Pub Date : 2025-10-02 DOI: 10.1016/j.str.2025.08.014

Fiyaz Mohammed, Carrie R. Willcox, Benjamin E. Willcox

引用次数: 0

Proteasome-associated autoinflammatory syndromes: The impact of mutations in proteasome subunits on particle assembly, structure, and activity 蛋白酶体相关的自身炎症综合征：蛋白酶体亚基突变对颗粒组装、结构和活性的影响

IF 5.7 2区生物学

Structure Pub Date : 2025-09-30 DOI: 10.1016/j.str.2025.09.004

Eva M. Huber, Wolfgang Heinemeyer, Michael Groll

{"title":"Proteasome-associated autoinflammatory syndromes: The impact of mutations in proteasome subunits on particle assembly, structure, and activity","authors":"Eva M. Huber, Wolfgang Heinemeyer, Michael Groll","doi":"10.1016/j.str.2025.09.004","DOIUrl":"https://doi.org/10.1016/j.str.2025.09.004","url":null,"abstract":"Single point mutations in proteasome subunits can cause severe autoinflammatory syndromes. By still largely unknown mechanisms, some of these disease-associated mutations impair normal proteasome function and induce the production of pro-inflammatory cytokines, thereby leading to systemic inflammations. In order to obtain more insights on why and how the mutations T3M and G128V in the immunoproteasome subunit β5i trigger such deleterious effects, we created the respective yeast mutants and characterized their phenotypes with special emphasis on proteasome structure and activity. X-ray crystallographic data revealed that the mutation T3M influences structure and flexibility of the proteasomal substrate-binding channel with moderate impairment of proteasome biogenesis, whereas the amino acid substitution G128V causes larger structural rearrangements that severely disturb particle assembly and maturation. The obtained results provide a deeper understanding of how single point mutations can affect proteasome subunit structure as well as particle biogenesis and ultimately cause chronic inflammatory diseases.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"100 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145189270","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Lipids modulate the open probability of RyR1 under cryo-EM conditions 在低温电镜条件下，脂质调节RyR1的打开概率

IF 5.7 2区生物学

Structure Pub Date : 2025-09-29 DOI: 10.1016/j.str.2025.09.003

Chenyao Li, Rouslan G. Efremov

引用次数: 0

Structural insights into IL-31 signaling inhibition by a neutralizing antibody 中和抗体对IL-31信号抑制的结构见解

IF 5.7 2区生物学

Structure Pub Date : 2025-09-26 DOI: 10.1016/j.str.2025.09.002

Tianling Guo, Yuxin Zheng, Zheng Fan, Ping Liu, Yan Chai, Xiaoping Liao, Caili Zhang, Xuefei Pang, Delin Li, Feng Gao, Haixia Xiao

{"title":"Structural insights into IL-31 signaling inhibition by a neutralizing antibody","authors":"Tianling Guo, Yuxin Zheng, Zheng Fan, Ping Liu, Yan Chai, Xiaoping Liao, Caili Zhang, Xuefei Pang, Delin Li, Feng Gao, Haixia Xiao","doi":"10.1016/j.str.2025.09.002","DOIUrl":"https://doi.org/10.1016/j.str.2025.09.002","url":null,"abstract":"Interleukin-31 (IL-31) signals through the IL-31 receptor alpha (IL-31RA) and oncostatin M receptor beta (OSMRβ) heterodimer, mediating pruritus, dermatitis, inflammatory responses, neuroimmune interactions, and certain cancers. Here, we present the crystal structure of canine IL-31 (cIL-31) in complex with a neutralizing caninized monoclonal antibody (2D10-2). This antibody competitively inhibited cIL-31 binding to canine OSMRβ (cOSMRβ) but not to canine IL-31RA (cIL-31RA). Moreover, it effectively blocked cIL-31-induced STAT5 phosphorylation <em>in vitro</em> and alleviated cIL-31-induced pruritus in beagle dogs. Structural analysis identified key antibody-binding residues in α-helical A, α-helical D, and the AB loop of cIL-31. Systematic mutagenesis based on the complex structure further defined the conformational epitopes of cIL-31 recognized by cOSMRβ. In summary, this study reports the IL-31 structure, revealing a four-α-helical bundle cytokine, and elucidates 2D10-2’s neutralizing mechanism by targeting the cIL-31-cOSMRβ interaction. These findings advance our understanding of IL-31 and offer insights for developing IL-31-targeted therapeutics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":"17 1","pages":""},"PeriodicalIF":5.7,"publicationDate":"2025-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145140951","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Flexibility or uncertainty? A critical assessment of AlphaFold 2 pLDDT 灵活性还是不确定性？AlphaFold 2 pLDDT的关键评估

IF 5.7 2区生物学

Structure Pub Date : 2025-09-25 DOI: 10.1016/j.str.2025.09.001

Yann Vander Meersche, Julien Diharce, Jean-Christophe Gelly, Tatiana Galochkina

引用次数: 0

The relationship between interfacial overlap and functional divergence in the yeast protein-protein interaction network 酵母蛋白-蛋白相互作用网络中界面重叠与功能分化的关系

IF 5.7 2区生物学

Structure Pub Date : 2025-09-17 DOI: 10.1016/j.str.2025.08.019

Yilun Han, Mohamed Ghadie, Yu Xia

引用次数: 0

Molecular basis of DNA recognition by the HMG-box-C1 module of capicua 卡皮藻HMG-box-C1模块DNA识别的分子基础

IF 5.7 2区生物学

Structure Pub Date : 2025-09-17 DOI: 10.1016/j.str.2025.08.018

Jonathan Webb, Jeremy J.M. Liew, Andrew D. Gnann, Khandan Ilkhani, MacKenzie Patterson, Sayantanee Paul, Marta Forés, Gerardo Jiménez, Alexey Veraksa, Daniel P. Dowling

引用次数: 0

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