Acta Crystallographica. Section D, Structural Biology最新文献

{"title":"Photoisomerization detected in a fully wavelength-tunable rhodopsin mimic system.","authors":"Nona Ehyaei, Courtney Bingham, Katelyn Silva, Zahra Nossoni, Hadi Nayebi Gavgani, Meisam Nosrati, Joelle Eaves, Mustapha Akhdar, Chrysoula Vasileiou, Babak Borhan, James H Geiger","doi":"10.1107/S2059798326003839","DOIUrl":"10.1107/S2059798326003839","url":null,"abstract":"<p><p>We describe the photoisomerization of the retinylidene protonated Schiff base in human retinol-binding protein II (hCRBPII) and the role of water molecules in this process. We characterize the photoisomerization of the 15-cis/all-trans retinylidene protonated Schiff base in this system using UV-visible spectroscopy and atomic-resolution X-ray crystallography. We further demonstrate a process where the pK_a of the protonated Schiff base is substantially altered by light-induced dehydration of the binding pocket, suggesting novel pathways of photoswitching that rely not on isomerization or conformational change of the chromophore but rather on light-induced reorganization of the protein environment.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"664-671"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224928/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148040659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Structural basis for high-affinity inhibitor binding to lipid kinases PIP4K2A and PIP4K2B.","authors":"Zunyu He, Song Chen, Fabrizio Micheli, Agostino Cianciulli, Claudia Beato, Jonathan Ellman, Ya Ha","doi":"10.1107/S2059798326003773","DOIUrl":"10.1107/S2059798326003773","url":null,"abstract":"<p><p>The phosphatidylinositol 5-phosphate 4-kinases (PIP4Ks) are an evolutionarily conserved family of lipid kinases that phosphorylate phosphatidylinositol 5-phosphate to generate phosphatidylinositol 4,5-bisphosphate. In mammals, the catalytically active α and β isoforms, encoded by PIP4K2A and PIP4K2B, respectively, localize to distinct cellular compartments and have been implicated in metabolism, immune regulation and tumorigenesis, prompting interest in their pharmacological inhibition. Notably, most reported small-molecule inhibitors display substantially higher potency towards the α isoform than the β isoform, suggesting intrinsic structural features that limit the effective targeting of PIP4K2B. Here, we report the crystal structure of PIP4K2A in complex with 422A, a potent dual α/β inhibitor with improved metabolic stability. The structure reveals an unexpected, water-mediated interaction in which a pyridyl nitrogen of the inhibitor engages a conserved structured water molecule in the roof of the specificity pocket, constraining the orientation of the pyridylmethyl side chain and stabilizing a rigid, high-affinity binding mode. Comparative structural analysis with the PIP4K2A-selective inhibitor BAY-091 shows that deeper penetration into the specificity pocket enhances PIP4K2A binding but is accompanied by local steric constraints that are likely to be less well tolerated in PIP4K2B. Together, these findings define structural determinants of isoform-dependent inhibitor binding within the PIP4K family and provide a framework for structure-guided optimization of lipid kinase inhibitors with improved isoform balance.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"646-654"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224930/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147872767","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Peptide binding at the gasdermin D exosite reveals the structural basis for targeting the site.","authors":"Renjing Wang, Thu Ho, Aimie Ogawa, Kartika Widjaja, Zachary Brown, Song Yang, Pei Huo, Michael C Gregory, Aman Singh, Senthil Perumal, Songnian Lin, Alan C Cheng, Lindsay S Garrenton, James Mu, Anthony Ogawa, Jill E Chrencik","doi":"10.1107/S205979832600344X","DOIUrl":"10.1107/S205979832600344X","url":null,"abstract":"<p><p>Gasdermin D (GSDMD) has been identified as a critical component of the inflammasome, an important intracellular signaling multi-protein complex. Abnormal activation of GSDMD has been linked to a variety of inflammatory diseases, including non-alcoholic steatohepatitis, inflammatory bowel disease and COVID-19, and has been linked to potential pathogenesis of septic shock. While small molecules have been identified to inhibit N-terminal domain (NTD) pore formation and membrane translocation, further clinical application of these molecules is currently limited due to narrow specificity. Here, we report a peptide from a structure-based computational screen that selectively inhibits caspase-dependent cleavage of GSDMD. We have determined the structure of the GSDMD-peptide complex, indicating that peptide binding is facilitated by negatively charged residues from the peptide and the hydrophobic exosite of the protein, inhibiting caspase binding and activation. The experimental data suggest the potential to target the exosite for therapeutic intervention.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"615-625"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224929/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147925425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The evolving role of structural biology in pharma: integration of X-ray crystallography, cryo-electron microscopy and beyond.","authors":"Jill E Chrencik, Hua Poo Su, Yacob Gomez Llorente, Rachel L Palte, Daniel J Klein, Robert P Hayes, Sadie P Antine, Guilermo A Asmar-Rovira, Nicole Bertoletti, Noel J Byrne, Brittany L Carroll, Ciro D Cordeiro, Kaylynn Curfman, James Dutko, Michael J Eddins, Thierry Fischmann, Barani Govindarajan, Corey W Hecksel, Thu Ho, Kaspar Hollenstein, Mee Ra Hong, Alan Hruza, Andrii Ishchenko, Maru Jaime-Garza, Matt J Jaremko, Hayley L Knox, James Kostas, Harini Krishnamurthy, Ioannis Manolaridis, Cameron L Noland, Andrea T Partridge, Sangita B Patel, Paul Reichert, John C Reid, Catarina Felisberto-Rodrigues, Chitra A Shintre, Jennifer M Shipman, Elakkiya Tamilselvan, Morgan E Walker, Susanne N Walker, Renjing Wang, Katharine M Wright, Tien Jui Yen, Byung Kuk Yoo, Sandra B Gabelli","doi":"10.1107/S2059798326004390","DOIUrl":"10.1107/S2059798326004390","url":null,"abstract":"<p><p>Structural biology has fundamentally influenced pharmaceutical research and development at Merck Sharp & Dohme LLC, Rahway, New Jersey, USA, progressing from pioneering macromolecular crystallography in the 1980s to a fully integrated platform that today encompasses X-ray crystallography, cryo-electron microscopy, micro-electron diffraction and cryo-electron tomography. In this review, we present a comprehensive overview of how these complementary methods have advanced drug discovery across diverse therapeutic areas. We illustrate how atomic to cellular structural insights inform drug discovery and development, from target identification and validation, hit finding, lead identification through lead optimization and clinical progression. Furthermore, we describe how structural biology techniques aid in formulation strategies of antibodies and vaccines. Finally, we highlight the growing integration of ex situ and in situ approaches as a paradigm shift towards elucidating drug mechanisms in native cellular contexts, a transition poised to accelerate the discovery and development of next-generation therapeutics.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"587-602"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224919/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148025744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cryo-EM structure of ALC1 in an open conformation bound to a PARylated nucleosome.","authors":"Hannah R Bridges, Luka Bacic, Sebastian Deindl, Guillaume Gaullier","doi":"10.1107/S2059798326004158","DOIUrl":"10.1107/S2059798326004158","url":null,"abstract":"<p><p>Nucleosomes are the repeating unit of chromatin. They act as recognition platforms for chromatin-binding factors that coordinate genome maintenance. The chromatin remodeler Amplified in Liver Cancer 1 (ALC1) is a key component of the DNA-damage response and a promising therapeutic target in cancer. Through extensive classification of our previously deposited cryo-electron microscopy dataset, we identified a previously unresolved ALC1-nucleosome complex characterized by a more open conformation of ALC1. This is the first structure of ALC1 in which all domains are visualized in the context of a nucleosome complex, including the regulatory macro domain and a single α-helix motif within the linker. This newly identified conformation may represent an intermediate between the auto-inhibited and active states, and provides new structural insights into the conformational transitions that regulate the activity of ALC1.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"683-699"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147969556","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comment on Photosystem II: light-dependent oscillation of ligand composition at its active site: existence of O6 in S₃-state photosystem II revealed by omit maps.","authors":"Hongjie Li, Michihiro Suga, Jian Ren Shen","doi":"10.1107/S2059798326003621","DOIUrl":"10.1107/S2059798326003621","url":null,"abstract":"<p><p>Photosystem II (PSII) catalyzes the light-driven oxidation of water to molecular oxygen through a series of redox states (S₀-S₄) in the Kok cycle. This reaction is catalyzed by a Mn₄CaO₅ cluster bound to PSII in the dark-stable S₁ state, and insertion of a sixth oxygen ligand (O6) in the S₃ state has been shown to be a key step in O-O bond formation by multiple pump-probe X-ray free-electron laser (XFEL) studies. However, a recent reanalysis of the experimental XFEL data by Wang [(2024), Acta Cryst. D80, 850-861] challenged the existence of O6, attributing the observed difference electron density to an artifact arising from a two-conformer model of O5 instead of the insertion of a new oxygen O6. Here, we reanalyzed our 2F dataset using improved omit-map strategies, including conformation-specific analyses, and clearly resolved electron density corresponding to a partially occupied O6 site. Moreover, omit maps from time-resolved serial femtosecond X-ray crystallography datasets at room temperature revealed a transient intermediate (O6*) near the Ca site shortly after the second flash, which subsequently migrated to the O6 position. These findings provide structural evidence that supports the assignment of O6 as a state-specific ligand in the S₃ state, and are inconsistent with the interpretation proposed by Wang.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"574-586"},"PeriodicalIF":4.3,"publicationDate":"2026-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13224924/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147866298","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Optimal 1TEL-target protein linker character is target protein-dependent.","authors":"Maria J Pedroza Romo, Alihikaua Keliiliki, Jacob C Averett, Joseph F Gonzalez, Ethan Noakes, Elijah W Wilson, Conrad Smith, Blake Averett, Dalton Hansen, Riley Nickles, Miles Bradford, Sara Soleimani, Tobin Smith, Supeshala Nawarathnage, Prasadika Samarwickrama, Ariel Kelsch, Derick Bunn, Cameron Stewart, Wisdom Abiodun, Evan Tsubaki, Seth Brown, Tzanko I Doukov, James D Moody","doi":"10.1107/S2059798326002494","DOIUrl":"10.1107/S2059798326002494","url":null,"abstract":"<p><p>Fusing a variant of the sterile alpha motif domain of the human translocation ETS leukaemia protein (1TEL) to a protein of interest has been shown to significantly enhance its crystallization propensity. 1TEL is a pH-dependent, polymer-forming protein crystallization chaperone which, when covalently fused to a protein of interest, forms a stable, well ordered crystal lattice. However, despite its success, a challenge persists in that crystal quality and diffraction limits appear to be heavily dependent on the choice of linker between 1TEL and the protein of interest, with the identification of a functional linker currently relying on trial-and-error methods. Likewise, previous studies revealed that a ten-histidine tag at the 1TEL N-terminus can either facilitate or hinder the ordered crystallization of target proteins attached via flexible or semi-flexible linkers. To address these challenges, we designed multiple constructs with several types of linkers [rigid (helical fusion), semi-flexible (Pro-Ala and Pro-Ala-Ala) and flexible (Gly-Gly and Gly-Gly-Gly)] of varying lengths to fuse either a designed ankyrin-repeat protein (DARPin) or the thirty-eight-negative kinase-1 ubiquitin-associated (UBA) domain to the 1TEL C-terminus. Semi-flexible and flexible linker constructs were made with and without a ten-histidine tag. Our findings indicate that short semi-flexible and rigid linkers consistently yielded large crystals with a DARPin target protein, but that flexible linkers performed best with a UBA-domain target protein. Removing the ten-histidine tag uniformly enhanced crystallization rates, improved the crystal morphology and increased the crystallization propensity of the semi-flexible and flexible linker constructs. These results suggest that the ideal linker selection primarily depends on the properties of the target protein. Our data support our current recommendation to use a short flexible or semi-flexible linker between 1TEL and the target protein to facilitate protein crystallization and high-resolution structure determination.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"516-532"},"PeriodicalIF":4.3,"publicationDate":"2026-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13133986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147632461","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ICECREAM: high-fidelity equivariant cryo-electron tomography.","authors":"Vinith Kishore, Valentin Debarnot, Ricardo D Righetto, Benjamin D Engel, Ivan Dokmanić","doi":"10.1107/S2059798326001622","DOIUrl":"10.1107/S2059798326001622","url":null,"abstract":"<p><p>Cryo-electron tomography (cryo-ET) visualizes 3D cellular architecture in its near-native state. The various deep-learning methods have improved denoising and artifact correction, but remain challenged by a very low signal-to-noise ratio, a restricted tilt range (`missing wedge') and the lack of ground truth. Here, we present ICECREAM, which bridges earlier self-supervised methods with the recent equivariant imaging framework [Chen et al. (2021), IEEE/CVF International Conference on Computer Vision (ICCV), pp. 4359-4368]. Across diverse experimental datasets, ICECREAM achieves substantially better denoising and more reliable missing-wedge filling than existing methods. ICECREAM can be applied to any tomography problem that provides two statistically independent views of the volume; in cryo-ET these are obtained by dose splitting or angular partitioning of the tilt series. ICECREAM is openly available at https://github.com/swing-research/icecream.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"295-313"},"PeriodicalIF":4.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044925/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147525322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular structure and nickel-binding capacity of Proteus mirabilis UreE.","authors":"Jiayi Pan, Sarah L Mueller, Nuren Tasneem, Yang Wu, Emily J Furlong","doi":"10.1107/S2059798326001907","DOIUrl":"10.1107/S2059798326001907","url":null,"abstract":"<p><p>UreE is a nickel chaperone that is required for the safe and efficient delivery of nickel to the active site of the metalloenzyme urease, which is a key virulence factor of the urinary-tract pathogen Proteus mirabilis. We investigated the structural features of P. mirabilis UreE (PmUreE) using protein X-ray crystallography and its nickel-binding capacity by inductively coupled plasma mass spectrometry. Here, we report a 2.0 Å resolution crystal structure of homodimeric PmUreE and show that it has the capacity to bind five Ni(II) ions per dimer. Truncation of the histidine-rich C-terminus reduced the nickel-binding capacity by two Ni(II) ions per dimer, and comparison with homologous UreE structures allowed the assignment of putative nickel-binding sites within the PmUreE structure. These findings increase our understanding of how PmUreE binds nickel and ultimately prevents this toxic metal from causing significant cellular damage in P. mirabilis.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"348-357"},"PeriodicalIF":4.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044922/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147462514","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Crystal structures of Fsc1, a novel autophagy factor that mediates autophagosome-vacuole fusion in fission yeast.","authors":"Chidiogo Azuka, Jian Liu, Xiangshu Jin","doi":"10.1107/S205979832600197X","DOIUrl":"10.1107/S205979832600197X","url":null,"abstract":"<p><p>Fsc1 is a recently identified autophagy factor in the fission yeast Schizosaccharomyces pombe that is implicated in the autophagosome-vacuole fusion step during the final stages of autophagy. Despite its critical role, the structural basis of Fsc1 function has remained unknown. Here, we report the first crystal structures of the luminal domain of Fsc1, revealing an elongated, modular architecture composed of five tandem fasciclin (FAS1) domains. Each domain adopts a hallmark β-sandwich fold, and the overall assembly forms a continuous scaffold featuring a conserved surface groove within the FAS1-4 domain. Structural and biochemical analyses demonstrate that Fsc1 forms a homodimer in solution through a shared interface observed in two independent crystal forms, supporting a biologically relevant but potentially low-affinity association. Comparative sequence and structural analyses reveal significant homology between Fsc1 and human fasciclin proteins, including TGFBI and periostin, suggesting similar structural principles underlying their functions. Together, these findings provide the first structural insights into Fsc1 and establish a structural framework for understanding how its modular architecture and context-dependent dimerization may facilitate late-stage membrane fusion during autophagy.</p>","PeriodicalId":7116,"journal":{"name":"Acta Crystallographica. Section D, Structural Biology","volume":" ","pages":"358-369"},"PeriodicalIF":4.3,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13044898/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147508731","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}