IUCrJ最新文献

{"title":"Novel starting points for fragment-based drug design against human heat-shock protein 90 identified using crystallographic fragment screening","authors":"Liqing Huang ,&nbsp;Weiwei Wang ,&nbsp;Zhimin Zhu ,&nbsp;Qianhui Li ,&nbsp;Minjun Li ,&nbsp;Huan Zhou ,&nbsp;Qin Xu ,&nbsp;Wen Wen ,&nbsp;Qisheng Wang ,&nbsp;Feng Yu","doi":"10.1107/S2052252524012247","DOIUrl":"10.1107/S2052252524012247","url":null,"abstract":"<div><div>In this first instance of crystallographic fragment screening completed by the crystallographic fragment-screening platform of the Shanghai Synchrotron Radiation Facility (SSRF) in China, 800 fragments were screened and 91 compounds were identified to bind at eight different sites.</div></div><div><div>Heat-shock protein 90 (HSP90) is a highly active molecular chaperone that plays a crucial role in cellular function. It facilitates the folding, assembly and stability of various oncogenic proteins, particularly kinases and transcription factors involved in regulating tumor growth and maintenance signaling pathways. Consequently, HSP90 inhibitors are being explored as drugs for cancer therapy. Crystallographic fragment screening is a novel screening method that has been developed in recent years for fragment-based drug discovery and is known for its high hit rate and its ability to provide direct insights into the complex structures of proteins and compounds. In this paper, high-diffraction-resolution crystals of the N-terminal domain of human HSP90α were employed in crystallographic fragment screening to discover binding fragments and binding sites. A diverse library of 800 structurally distinct fragments was screened, yielding 91 starting points for the fragment-based drug design of new HSP90α N-terminal inhibitors. Nearly a thousand crystals were measured, with 738 being processed and phased using a highly automated data-processing pipeline including data reduction and phasing, refinement and hit identification via <em>PanDDA</em> multi-data-set analysis. The 91 identified compounds bind to eight distinct regions of the HSP90α N-terminus, with 63 fragments located in the ATP-binding pocket and its surroundings, thus demonstrating the potential for the development of HSP90α- and ATP-binding inhibitors. This study emphasizes crystallographic fragment screening as a powerful method that can effectively identify fragment molecules and inhibitors that bind to HSP90α, contributing to ongoing efforts in cancer drug discovery.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 177-187"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FLEXR-MSA: electron-density map comparisons of sequence-diverse structures","authors":"Timothy R. Stachowski ,&nbsp;Marcus Fischer","doi":"10.1107/S2052252525001332","DOIUrl":"10.1107/S2052252525001332","url":null,"abstract":"<div><div><em>FLEXR-MSA</em> extends the <em>FLEXR</em> suite of tools by enabling electron-density map comparisons of sequence-diverse proteins.</div></div><div><div>Proteins with near-identical sequences often share similar static structures. Yet, comparing crystal structures is limited or even biased by what has been included or omitted in the deposited model. Information about unique dynamics is often hidden in electron-density maps. Currently, automatic map comparisons are limited to sequence-identical structures. To overcome this limitation, we developed <em>FLEXR-MSA</em>, which enables unbiased electron-density map comparisons of sequence-diverse structures by coupling multiple sequence alignment (MSA) with electron-density sampling. <em>FLEXR-MSA</em> generates visualizations that pinpoint low-occupancy features on the residue level and chart them across the protein surface to reveal global changes. To exemplify the utility of this tool, we probed electron densities for protein-wide alternative conformations of HSP90 across four human isoforms and other homologs. Our analysis demonstrates that <em>FLEXR-MSA</em> can reveal hidden differences among HSP90 variants bound to clinically important ligands. Integrating this new functionality into the <em>FLEXR</em> suite of tools links the comparison of conformational landscapes hidden in electron-density maps to the building of multi-conformer models that reveal structural/functional differences that might be of interest when designing selective ligands.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 245-254"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Combining experiment and prediction to explore surface chemistry and dissolution","authors":"Andrew G. P. Maloney","doi":"10.1107/S2052252525001782","DOIUrl":"10.1107/S2052252525001782","url":null,"abstract":"<div><div>A crystal structure is often an integral component in the development of a new pharmaceutical product, and these structures are frequently used to understand, assess and often predict both the manufacturing and <em>in vivo</em> behaviour of these compounds. Combining a range of analytical methods with computational analysis of the crystal surfaces, Zmeškalová <em>et al.</em> [(2025). <em>IUCrJ</em>, <strong>12</strong>, 141–154] link the properties of three solid forms of a biologically active molecule to its dissolution behaviour.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 137-138"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143515745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"On interrogating electron microscopy images to discover proteins in the cell","authors":"Jose-Maria Carazo","doi":"10.1107/S2052252525001861","DOIUrl":"10.1107/S2052252525001861","url":null,"abstract":"<div><div>Interrogating individual two-dimensional (2D) cryo-EM images for the presence of defined three-dimensional (3D) structures that correspond to previously known (or predicted) macromolecular complexes is very challenging, but offers attractive opportunities for the analysis of large numbers of specimens. The work of Zhang <em>et al.</em>[(2025), <em>IUCrJ</em>, <strong>12</strong>, 155–176] represents a significant step forward towards this goal.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 139-140"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-shot X-ray imaging of two-dimensional strain fields in colloidal crystals","authors":"Jiecheng Diao ,&nbsp;Zichen Gao ,&nbsp;Jiadong Fan ,&nbsp;Yajun Tong ,&nbsp;Hang Ren ,&nbsp;Yonggan Nie ,&nbsp;Ian Robinson ,&nbsp;Huaidong Jiang","doi":"10.1107/S2052252524012521","DOIUrl":"10.1107/S2052252524012521","url":null,"abstract":"<div><div>We used the Bragg coherent diffraction imaging method at the Coherent Scattering and Imaging endstation of the Shanghai Soft X-ray Free Electron Laser Facility to characterize colloidal crystals. This method successfully reproduced the static shape of crystals and we observed the defect structure of colloidal samples.</div></div><div><div>We used a soft X-ray free-electron laser and the Bragg coherent diffraction imaging method to characterize the defect structure of colloidal crystals. The single-shot X-ray pulse allowed us to reach four powder rings and measured all six reflections of the hexagonal lattice. We reproduced the static shape of the 2D crystal and mapped out the 2D strain tensors inside the crystal. The observed defect structures agreed with electron microscope images of similar colloidal samples.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 239-244"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391038","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Understanding the selectivity of nonsteroidal anti-inflammatory drugs for cyclooxygenases using quantum crystallography and electrostatic interaction energy","authors":"S. Pawlędzio ,&nbsp;M. Ziemniak ,&nbsp;X. Wang ,&nbsp;K. Woźniak ,&nbsp;M. Malinska","doi":"10.1107/S2052252525000053","DOIUrl":"10.1107/S2052252525000053","url":null,"abstract":"<div><div>This study employs quantum crystallography to elucidate the selectivity of nonsteroidal anti-inflammatory drugs (NSAIDs), including ibuprofen, flurbiprofen, meloxicam and celecoxib, for cyclooxygenase-1 and cyclooxygenase-2 enzymes by analyzing binding energy and electrostatic interactions. The findings reveal key structural determinants of NSAID selectivity, providing valuable insights for the rational design of safer and more effective anti-inflammatory drugs.</div></div><div><div>Quantum crystallography methods have been employed to investigate complex formation between nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX) enzymes, with particular focus on the COX-1 and COX-2 isoforms. This study analyzed the electrostatic interaction energies of selected NSAIDs (flurbiprofen, ibuprofen, meloxicam and celecoxib) with the active sites of COX-1 and COX-2, revealing significant differences in binding profiles. Flurbiprofen exhibited the strongest interactions with both COX-1 and COX-2, indicating its potent binding affinity. Celecoxib and meloxicam showed a preference for COX-2, consistent with their known selectivity for this isoform, while ibuprofen showed comparable interaction energies with both isoforms, reflecting its nonselective inhibition pattern. Key amino-acid residues, including Arg120, Arg/His513 and Tyr355, were identified as critical determinants of NSAID selectivity and binding affinity. The findings highlight the complex interplay between interaction energy and selectivity, suggesting that while electrostatic interactions play a fundamental role, additional factors such as enzyme dynamics and the hydrophobic effect also contribute to the therapeutic efficacy and safety profiles of NSAIDs. These insights provide valuable guidance for the rational design of NSAIDs with enhanced therapeutic benefits and minimized adverse effects.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 208-222"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065735","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The nature of halogen bonding: insights from interacting quantum atoms and source function studies","authors":"Arianna Pisati ,&nbsp;Alessandra Forni ,&nbsp;Stefano Pieraccini ,&nbsp;Maurizio Sironi","doi":"10.1107/S2052252525000363","DOIUrl":"10.1107/S2052252525000363","url":null,"abstract":"<div><div>Interacting quantum atoms and source function studies on a series of halogen-bonded complexes between substituted pyridines and <em>X</em>₂ or <em>X</em>CN molecules (<em>X</em> = I, Br) focus on the combined role played by the <em>X</em> and N interacting pairs and their local environment.</div></div><div><div>A detailed study of the <em>X</em>⋯N (<em>X</em> = I, Br) halogen bonds in complexes formed by an extended set of substituted pyridines with <em>D</em>—<em>X</em> molecules (<em>D</em> = <em>X</em>, CN) is reported here. The nature of these interactions has been investigated at different (MP2 and DFT) levels of theory through Bader’s quantum theory of atoms in molecules (QTAIM) and Pendás’ interacting quantum atoms (IQA) scheme, focusing on the role of the local environment (<em>i.e.</em> the substituent on the pyridine ring and the halogenated residue) on the halogen bond features. We found that the exchange-correlation energy represents a substantial contribution to the IQA total energy, in some cases comparable to (I₂ complexes) or even dominating (ICN complexes) the electrostatic term. Meaningful information is provided by the source function, indicating that the major contribution to the electron density at the bond critical point of the <em>X</em>⋯N interaction is derived from the halogen atom, while a much lower contribution comes from the nitro­gen atom, which acts as either source or sink for electron density. A relevant contribution from distal atoms, including the various electron-donor and electron-withdrawing substituents in different positions of the pyridine ring, is also determined, highlighting the non-local character of the electron density. The existence of possible relationships between binding energies, interaction energies according to IQA, and QTAIM descriptors such as delocalization indices and source function, has been inspected. In general, good correlations are only found when the local environment, external to the directly involved halogen and nitro­gen atoms, plays a minor role in the interaction.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 188-197"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143052659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Experimental electronic structures of copper complexes with a bi­phenyldi­imino di­thio­ether – a model for blue copper proteins","authors":"Marek Fronc ,&nbsp;Martin Breza ,&nbsp;Lukáš Bučinský ,&nbsp;Ingrid Jelemenská ,&nbsp;Jozef Kožíšek","doi":"10.1107/S2052252524012107","DOIUrl":"10.1107/S2052252524012107","url":null,"abstract":"<div><div>Differences in the electronic structures of Cu(I) and Cu(II) coordination compounds with the same ligand are studied. These compounds act as a model for blue copper proteins.</div></div><div><div>The experimental electron density distributions in two coordination compounds – one with a central Cu(I) atom and the other with Cu(II), coordinated by the same bi­phenyldi­imino di­thio­ether (<em>bite</em>) type of ligand – have been obtained from high-resolution X-ray reflection data to model the possible electron predisposition for the redox reaction in blue copper proteins. The <em>bite</em> ligand has been adapted to the conformation required by the central atom.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 198-207"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143065732","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A new statistical metric for robust target detection in cryo-EM using 2D template matching","authors":"Kexin Zhang ,&nbsp;Pilar Cossio ,&nbsp;Aaditya V. Rangan ,&nbsp;Bronwyn A. Lucas ,&nbsp;Nikolaus Grigorieff","doi":"10.1107/S2052252524011771","DOIUrl":"10.1107/S2052252524011771","url":null,"abstract":"<div><div>A novel statistical metric for 2D template matching (2DTM), the 2DTM <em>p</em>-value, has been developed to improve the detection of targets in cryo-EM images under various imaging and sample conditions, particularly for smaller and aspherical targets.</div></div><div><div>2D template matching (2DTM) can be used to detect molecules and their assemblies in cellular cryo-EM images with high positional and orientational accuracy. While 2DTM successfully detects spherical targets such as large ribosomal subunits, challenges remain in detecting smaller and more aspherical targets in various environments. In this work, a novel 2DTM metric, referred to as the 2DTM <em>p</em>-value, is developed to extend the 2DTM framework to more complex applications. The 2DTM <em>p</em>-value combines information from two previously used 2DTM metrics, namely the 2DTM signal-to-noise ratio (SNR) and <em>z</em>-score, which are derived from the cross-correlation coefficient between the target and the template. The 2DTM <em>p</em>-value demonstrates robust detection accuracies under various imaging and sample conditions and outperforms the 2DTM SNR and <em>z</em>-score alone. Specifically, the 2DTM <em>p</em>-value improves the detection of aspherical targets such as a modified artificial tubulin patch particle (500 kDa) and a much smaller clathrin monomer (193 kDa) in simulated data. It also accurately recovers mature 60S ribosomes in yeast lamellae samples, even under conditions of increased Gaussian noise. The new metric will enable the detection of a wider variety of targets in both purified and cellular samples through 2DTM.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 155-176"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143005578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Accounting for electron-beam-induced warping of molecular nanocrystals in MicroED structure determination","authors":"Niko Vlahakis ,&nbsp;Arden Clauss ,&nbsp;Jose A. Rodriguez","doi":"10.1107/S2052252524012132","DOIUrl":"10.1107/S2052252524012132","url":null,"abstract":"<div><div>Here we identify and characterize the warping of molecular crystal lattices induced by electron beam exposure during microcrystal electron diffraction (MicroED/3DED) data collection. We find changes to consensus crystal lattice orientation that are often dramatic, and appear ubiquitous in small organic molecule crystals. This evidence highlights the relevance of crystal bending or warping as a consequence of radiation-induced damage on molecular specimens, and points to it as a fundamental source of error in MicroED/3DED data collection and structure determination.</div></div><div><div>High-energy electrons induce sample damage and motion at the nanoscale to fundamentally limit the determination of molecular structures by electron diffraction. Using a fast event-based electron counting (EBEC) detector, we characterize beam-induced, dynamic, molecular crystal lattice reorientations (BIRs). These changes are sufficiently large to bring reciprocal lattice points entirely in or out of intersection with the sphere of reflection, occur as early events in the decay of diffracted signal due to radiolytic damage, and coincide with beam-induced migrations of crystal bend contours within the same fluence regime and at the same illuminated location on a crystal. These effects are observed in crystals of biotin, a series of amino acid metal chelates, and a six-residue peptide, suggesting that incident electrons inevitably warp molecular lattices. The precise orientation changes experienced by a given microcrystal are unpredictable but are measurable by indexing individual diffraction patterns during beam-induced decay. Reorientations can often tilt a crystal lattice several degrees away from its initial position before irradiation, and for an especially beam-sensitive Zn(II)-me­thio­nine chelate, are associated with dramatic crystal quakes prior to 1 e⁻ Å⁻² electron beam fluence accumulates. Since BIR coincides with the early stages of beam-induced damage, it echoes the beam-induced motion observed in single-particle cryoEM. As with motion correction for cryoEM imaging experiments, accounting for BIR-induced errors during data processing could improve the accuracy of MicroED data.</div></div>","PeriodicalId":14775,"journal":{"name":"IUCrJ","volume":"12 2","pages":"Pages 223-238"},"PeriodicalIF":2.9,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382365","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"材料科学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}