StructurePub Date : 2024-10-16DOI: 10.1016/j.str.2024.09.019
Robert Karari Njenga, Julian Boele, Friedel Drepper, Kasturica Sinha, Eirini Marouda, Pitter F. Huesgen, Crysten Blaby-Haas, Hans-Georg Koch
{"title":"Ribosome-inactivation by a class of widely distributed C-tail anchored membrane proteins","authors":"Robert Karari Njenga, Julian Boele, Friedel Drepper, Kasturica Sinha, Eirini Marouda, Pitter F. Huesgen, Crysten Blaby-Haas, Hans-Georg Koch","doi":"10.1016/j.str.2024.09.019","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.019","url":null,"abstract":"Ribosome hibernation is a commonly used strategy that protects ribosomes under unfavorable conditions and regulates developmental processes. Multiple ribosome-hibernation factors have been identified in all domains of life, but due to their structural diversity and the lack of a common inactivation mechanism, it is currently unknown how many different hibernation factors exist. Here, we show that the YqjD/ElaB/YgaM paralogs, initially discovered as membrane-bound ribosome binding proteins in <em>E. coli</em>, constitute an abundant class of ribosome-hibernating proteins, which are conserved across all proteobacteria and some other bacterial phyla. Our data demonstrate that they inhibit <em>in vitro</em> protein synthesis by interacting with the 50S ribosomal subunit. <em>In vivo</em> cross-linking combined with mass spectrometry revealed their specific interactions with proteins surrounding the ribosomal tunnel exit and even their penetration into the ribosomal tunnel. Thus, YqjD/ElaB/YgaM inhibit translation by blocking the ribosomal tunnel and thus mimic the activity of antimicrobial peptides and macrolide antibiotics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440034","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}
StructurePub Date : 2024-10-16DOI: 10.1016/j.str.2024.09.020
Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler, Arnaud Baslé, Martin E.M. Noble, Jane A. Endicott, Ehmke Pohl, Natalie J. Tatum
{"title":"Structural requirements for the specific binding of CRABP2 to cyclin D3","authors":"Martyna W. Pastok, Charles W.E. Tomlinson, Shannon Turberville, Abbey M. Butler, Arnaud Baslé, Martin E.M. Noble, Jane A. Endicott, Ehmke Pohl, Natalie J. Tatum","doi":"10.1016/j.str.2024.09.020","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.020","url":null,"abstract":"Cellular retinoic acid binding protein 2 (CRABP2) transports retinoic acid from the cytoplasm to the nucleus where it then transfers its cargo to retinoic acid receptor-containing complexes leading to activation of gene transcription. We demonstrate using purified proteins that CRABP2 is also a cyclin D3-specific binding protein and that the CRABP2 cyclin D3 binding site and the proposed CRABP2 nuclear localization sequence overlap. Both sequences are within the helix-loop-helix motif that forms a lid to the retinoic acid binding pocket. Mutations within this sequence that block both cyclin D3 and retinoic acid binding promote formation of a CRABP2 structure in which the retinoic acid binding pocket is occupied by an alternative lid conformation. Structural and functional analysis of CRABP2 and cyclin D3 mutants combined with AlphaFold models of the ternary CDK4/6-cyclin D3-CRABP2 complex supports the identification of an α-helical protein binding site on the cyclin D3 C-terminal cyclin box fold.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142440035","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}
StructurePub Date : 2024-10-14DOI: 10.1016/j.str.2024.09.006
Sateja Paradkar, Julia Purcell, Annie Cui, Sam Friedman, Katelyn J. Noronha, Matthew A. Murray, Ranjini K. Sundaram, Ranjit S. Bindra, Ryan B. Jensen
{"title":"PARG inhibition induces nuclear aggregation of PARylated PARP1","authors":"Sateja Paradkar, Julia Purcell, Annie Cui, Sam Friedman, Katelyn J. Noronha, Matthew A. Murray, Ranjini K. Sundaram, Ranjit S. Bindra, Ryan B. Jensen","doi":"10.1016/j.str.2024.09.006","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.006","url":null,"abstract":"Poly (ADP-ribose) glycohydrolase (PARG) inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers; however, their precise mechanism of action is still unclear. Here, we report that PARG inhibition leads to excessive PARylated poly (ADP-ribose) polymerase 1 (PARP1) reducing the ability of PARP1 to properly localize to sites of DNA damage. Strikingly, the mis-localized PARP1 accumulates as aggregates throughout the nucleus. Abrogation of the catalytic activity of PARP1 prevents aggregate formation, indicating that PAR chains play a key role in this process. Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142431228","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}
StructurePub Date : 2024-10-11DOI: 10.1016/j.str.2024.09.018
Jorge Fernandez-Perez, Akinobu Senoo, Jose M.M. Caaveiro, Makoto Nakakido, Susana de Vega, Ichiro Nakagawa, Kouhei Tsumoto
{"title":"Structural basis for the ligand promiscuity of the hydroxamate siderophore binding protein FtsB from Streptococcus pyogenes","authors":"Jorge Fernandez-Perez, Akinobu Senoo, Jose M.M. Caaveiro, Makoto Nakakido, Susana de Vega, Ichiro Nakagawa, Kouhei Tsumoto","doi":"10.1016/j.str.2024.09.018","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.018","url":null,"abstract":"Pathogenic bacteria must secure the uptake of nutritional metals such as iron for their growth, making their import systems attractive targets for the development of new antimicrobial modalities. In the pathogenic bacterium <em>Streptococcus pyogenes,</em> the iron uptake system FtsABCD transports iron encapsulated by siderophores of the hydroxamate class. However, the inability of <em>S. pyogenes</em> to produce these metabolites makes the biological and clinical relevance of this route unresolved. Herein, we demonstrated that the periplasmic binding protein FtsB recognizes not only the hydroxamate siderophore ferrichrome, as previously documented, but also ferrioxamine E (FOE), ferrioxamine B (FOB), and bisucaberin (BIS), each of them with high affinity (nM level). Up to seven aromatic residues in the binding pocket accommodate the variable backbones of the different siderophores through CH-π interactions, explaining ligand promiscuity. Collectively, our observations revealed how <em>S. pyogenes</em> exploits the diverse xenosiderophores produced by other microorganisms as iron sources to secure this precious nutrient.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142405131","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}
StructurePub Date : 2024-10-10DOI: 10.1016/j.str.2024.09.017
Tessa Keenan, Andrew R. Cowan, Emily K.P. Flack, Natasha E. Hatton, Abigail J. Walklett, Gavin H. Thomas, Glyn R. Hemsworth, Martin A. Fascione
{"title":"Structural dissection of the CMP-pseudaminic acid synthetase, PseF","authors":"Tessa Keenan, Andrew R. Cowan, Emily K.P. Flack, Natasha E. Hatton, Abigail J. Walklett, Gavin H. Thomas, Glyn R. Hemsworth, Martin A. Fascione","doi":"10.1016/j.str.2024.09.017","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.017","url":null,"abstract":"Pseudaminic acid is a non-mammalian sugar found in the surface glycoconjugates of many bacteria, including several human pathogens, and is a virulence factor thought to facilitate immune evasion. The final step in the biosynthesis of the nucleotide activated form of the sugar, CMP-Pse5Ac7Ac is performed by a CMP-Pse5Ac7Ac synthetase (PseF). Here we present the biochemical and structural characterization of PseF from <em>Aeromonas caviae</em> (AcPseF), with AcPseF displaying metal-dependent activity over a broad pH and temperature range. Upon binding to CMP-Pse5Ac7Ac, AcPseF undergoes dynamic movements akin to other CMP-ulosonic acid synthetases. The enzyme clearly discriminates Pse5Ac7Ac from other ulosonic acids, through active site interactions with side-chain functional groups and by positioning the molecule in a hydrophobic pocket. Finally, we show that AcPseF binds the CMP-Pse5Ac7Ac side chain in the lowest energy conformation, a trend that we observed in the structures of other enzymes of this class.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142398287","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}
StructurePub Date : 2024-10-09DOI: 10.1016/j.str.2024.09.016
Andrew D. Huber, Wenwei Lin, Shyaron Poudel, Darcie J. Miller, Taosheng Chen
{"title":"PROTAC-mediated activation, rather than degradation, of a nuclear receptor reveals complex ligand-receptor interaction network","authors":"Andrew D. Huber, Wenwei Lin, Shyaron Poudel, Darcie J. Miller, Taosheng Chen","doi":"10.1016/j.str.2024.09.016","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.016","url":null,"abstract":"Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules containing a ligand for a protein of interest linked to an E3 ubiquitin ligase ligand that induce protein degradation through E3 recruitment to the target protein. Small changes in PROTAC linkers can have drastic consequences, including loss of degradation activity, but the structural mechanisms governing such changes are unclear. To study this phenomenon, we screened PROTACs of diverse targeting modalities and identified dTAG-13 as an activator of the xenobiotic-sensing pregnane X receptor (PXR), which promiscuously binds various ligands. Characterization of dTAG-13 analogs and precursors revealed interplay between the PXR-binding moiety, linker, and E3 ligand that altered PXR activity without inducing degradation. A crystal structure of PXR ligand binding domain bound to a precursor ligand showed ligand-induced binding pocket distortions and a linker-punctured tunnel to the protein exterior at a region incompatible with E3 complex formation, highlighting the effects of linker environment on PROTAC activity.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142385777","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}
StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.015
Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio
{"title":"Cryo-EM structures of Clostridium perfringens enterotoxin bound to its human receptor, claudin-4","authors":"Sewwandi S. Rathnayake, Satchal K. Erramilli, Anthony A. Kossiakoff, Alex J. Vecchio","doi":"10.1016/j.str.2024.09.015","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.015","url":null,"abstract":"<em>Clostridium perfringens</em> enterotoxin (CpE) causes prevalent and deadly gastrointestinal disorders. CpE binds to receptors called claudins on the apical surfaces of small intestinal epithelium. Claudins normally regulate paracellular transport but are hijacked from doing so by CpE and are instead led to form claudin/CpE complexes. Claudin/CpE complexes are the building blocks of oligomeric β-barrel pores that penetrate the plasma membrane and induce gut cytotoxicity. Here, we present the structures of CpE in complex with its native claudin receptor in humans, claudin-4, using cryogenic electron microscopy. The structures reveal the architecture of the claudin/CpE complex, the residues used in binding, the orientation of CpE relative to the membrane, and CpE-induced changes to claudin-4. Further, structures and modeling allude to the biophysical procession from claudin/CpE complexes to cytotoxic β-barrel pores during pathogenesis. In full, this work proposes a model of claudin/CpE assembly and provides strategies to obstruct its formation to treat CpE diseases.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384294","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}
StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.013
Vladyslava Sokolova, Jacob Miratsky, Vladimir Svetlov, Michael Brenowitz, John Vant, Tyler S. Lewis, Kelly Dryden, Gahyun Lee, Shayan Sarkar, Evgeny Nudler, Abhishek Singharoy, Dongyan Tan
{"title":"Structural mechanism of HP1⍺-dependent transcriptional repression and chromatin compaction","authors":"Vladyslava Sokolova, Jacob Miratsky, Vladimir Svetlov, Michael Brenowitz, John Vant, Tyler S. Lewis, Kelly Dryden, Gahyun Lee, Shayan Sarkar, Evgeny Nudler, Abhishek Singharoy, Dongyan Tan","doi":"10.1016/j.str.2024.09.013","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.013","url":null,"abstract":"Heterochromatin protein 1 (HP1) plays a central role in establishing and maintaining constitutive heterochromatin. However, the mechanisms underlying HP1-nucleosome interactions and their contributions to heterochromatin functions remain elusive. Here, we present the cryoelectron microscopy (cryo-EM) structure of an HP1α dimer bound to an H2A.Z-nucleosome, revealing two distinct HP1α-nucleosome interfaces. The primary HP1α binding site is located at the N terminus of histone H3, specifically at the trimethylated lysine 9 (K9me3) region, while a secondary binding site is situated near histone H2B, close to nucleosome superhelical location 4 (SHL4). Our biochemical data further demonstrates that HP1α binding influences the dynamics of DNA on the nucleosome. It promotes DNA unwrapping near the nucleosome entry and exit sites while concurrently restricting DNA accessibility in the vicinity of SHL4. Our study offers a model for HP1α-mediated heterochromatin maintenance and gene silencing. It also sheds light on the H3K9me-independent role of HP1 in responding to DNA damage.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384295","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}
StructurePub Date : 2024-10-08DOI: 10.1016/j.str.2024.09.014
Nikita A. Egorkin, Eva E. Dominnik, Roman I. Raevskii, Daria D. Kuklina, Larisa A. Varfolomeeva, Vladimir O. Popov, Konstantin M. Boyko, Nikolai N. Sluchanko
{"title":"Structural basis of selective beta-carotene binding by a soluble protein","authors":"Nikita A. Egorkin, Eva E. Dominnik, Roman I. Raevskii, Daria D. Kuklina, Larisa A. Varfolomeeva, Vladimir O. Popov, Konstantin M. Boyko, Nikolai N. Sluchanko","doi":"10.1016/j.str.2024.09.014","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.014","url":null,"abstract":"β-carotene (BCR) is the most abundant carotenoid, a colorant, antioxidant, and provitamin A. The extreme hydrophobicity of this hydrocarbon requires special mechanisms for distribution in aqueous media, including water-soluble carotenoproteins. However, all known carotenoproteins prefer oxygenated carotenoids and bind BCR inefficiently. Here, we present the crystal structure of the BCR-binding protein (BBP) from gregarious male locusts, which is responsible for their vivid yellow body coloration, in complex with its natural ligand, BCR. BBP forms an antiparallel tubular homodimer with α/β-wrap folded monomers, each forming a hydrophobic 47 Å long, coaxial tunnel that opens outward and is occupied by one s-cis<sup>C6-C7</sup>, all-trans BCR molecule. In the BCR absence, BBP accepts a range of xanthophylls, with reduced efficiency depending on the position and number of oxygen atoms, but rejects lycopene. The structure captures a pigment complex with a Takeout 1 protein and inspires potential applications of BBP as a BCR solubilizer.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142384334","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}
{"title":"Structural biology of the human papillomavirus","authors":"Feng Han, Xin-ying Guo, Ming-xia Jiang, Ning-shao Xia, Ying Gu, Shao-wei Li","doi":"10.1016/j.str.2024.09.011","DOIUrl":"https://doi.org/10.1016/j.str.2024.09.011","url":null,"abstract":"Human papillomavirus (HPV), known for its oncogenic properties, is the primary cause of cervical cancer and significantly contributes to mortality rates. It also plays a considerable role in the globally rising incidences of head and neck cancers. These cancers pose a substantial health burden worldwide. Current limitations in diagnostic and treatment strategies, along with inadequate coverage of preventive vaccines in low- and middle-income countries, hinder the progress toward the World Health Organization (WHO) HPV prevention and control targets set for 2030. In response to these challenges, extensive research in structural virology has explored the properties of HPV proteins, yielding crucial insights into the mechanisms of HPV infection that are important for the development of prevention and therapeutic strategies. This review highlights recent advances in understanding the structures of HPV proteins and discusses achievements and future opportunities for HPV vaccine development.","PeriodicalId":22168,"journal":{"name":"Structure","volume":null,"pages":null},"PeriodicalIF":5.7,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142374099","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}