IUCrJ最新文献

英文中文

Novel starting points for fragment-based drug design against human heat-shock protein 90 identified using crystallographic fragment screening 利用晶体学片段筛选鉴定的针对人热休克蛋白90的基于片段的药物设计的新起点。

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252524012247

Liqing Huang , Weiwei Wang , Zhimin Zhu , Qianhui Li , Minjun Li , Huan Zhou , Qin Xu , Wen Wen , Qisheng Wang , Feng Yu

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.

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 PanDDA 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.

热休克蛋白90 （HSP90）是一种高活性的分子伴侣，在细胞功能中起着至关重要的作用。它促进了各种致癌蛋白的折叠、组装和稳定性，特别是参与调节肿瘤生长和维持信号通路的激酶和转录因子。因此，HSP90抑制剂正在被探索作为癌症治疗的药物。晶体片段筛选是近年来发展起来的一种基于片段的药物发现的新型筛选方法，以其高命中率和对蛋白质和化合物复杂结构的直接洞察能力而闻名。本文利用人HSP90α n端结构域的高衍射分辨率晶体进行晶体片段筛选，发现结合片段和结合位点。筛选了800个结构不同的片段，为新的HSP90α n端抑制剂的基于片段的药物设计提供了91个起点。测量了近一千个晶体，其中738个晶体使用高度自动化的数据处理管道进行处理和分相，包括通过panda多数据集分析进行数据简化和分相，细化和命中识别。鉴定出的91个化合物与HSP90α n端8个不同的区域结合，其中63个片段位于atp结合袋及其周围，从而显示了开发HSP90α和atp结合抑制剂的潜力。本研究强调晶体片段筛选是一种强大的方法，可以有效地识别与HSP90α结合的片段分子和抑制剂，有助于癌症药物的持续发现。

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引用次数: 0

FLEXR-MSA: electron-density map comparisons of sequence-diverse structures

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252525001332

Timothy R. Stachowski , Marcus Fischer

FLEXR-MSA extends the FLEXR suite of tools by enabling electron-density map comparisons of sequence-diverse proteins.

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 FLEXR-MSA, which enables unbiased electron-density map comparisons of sequence-diverse structures by coupling multiple sequence alignment (MSA) with electron-density sampling. FLEXR-MSA 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 FLEXR-MSA can reveal hidden differences among HSP90 variants bound to clinically important ligands. Integrating this new functionality into the FLEXR 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.

具有近乎相同序列的蛋白质往往具有相似的静态结构。然而，晶体结构的比较受到沉积模型中包含或遗漏内容的限制，甚至会产生偏差。独特的动力学信息往往隐藏在电子密度图中。目前，自动图谱比较仅限于序列相同的结构。为了克服这一局限，我们开发了FLEXR-MSA，通过将多序列比对（MSA）与电子密度采样相结合，实现了对序列不同的结构进行无偏见的电子密度图比较。FLEXR-MSA生成的可视化图谱可以精确定位残基水平上的低占位特征，并将其绘制成整个蛋白质表面的图谱，从而揭示全局变化。为了体现这一工具的实用性，我们探测了四种人类异构体和其他同源物中 HSP90 的全蛋白质替代构象的电子密度。我们的分析表明，FLEXR-MSA 可以揭示与临床重要配体结合的 HSP90 变体之间隐藏的差异。将这一新功能集成到 FLEXR 工具套件中，可将电子密度图中隐藏的构象图谱的比较与多构象模型的构建联系起来，从而揭示设计选择性配体时可能感兴趣的结构/功能差异。

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引用次数: 0

Combining experiment and prediction to explore surface chemistry and dissolution

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252525001782

Andrew G. P. Maloney

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 in vivo behaviour of these compounds. Combining a range of analytical methods with computational analysis of the crystal surfaces, Zmeškalová et al. [(2025). IUCrJ, 12, 141–154] link the properties of three solid forms of a biologically active molecule to its dissolution behaviour.

晶体结构通常是新药研发中不可或缺的组成部分，这些结构经常被用来了解、评估和预测这些化合物的生产和体内行为。Zmeškalová 等人将一系列分析方法与晶体表面的计算分析相结合[(2025). IUCrJ, 12, https://doi.org/10.1107/S2052252525001009]，将一种生物活性分子的三种固态形式的特性与其溶解行为联系起来。

引用次数: 0

On interrogating electron microscopy images to discover proteins in the cell

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252525001861

Jose-Maria Carazo

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 et al.[(2025), IUCrJ, 12, 155–176] represents a significant step forward towards this goal.

引用次数: 0

Single-shot X-ray imaging of two-dimensional strain fields in colloidal crystals

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252524012521

Jiecheng Diao , Zichen Gao , Jiadong Fan , Yajun Tong , Hang Ren , Yonggan Nie , Ian Robinson , Huaidong Jiang

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.

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.

引用次数: 0

Understanding the selectivity of nonsteroidal anti-inflammatory drugs for cyclooxygenases using quantum crystallography and electrostatic interaction energy

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252525000053

S. Pawlędzio , M. Ziemniak , X. Wang , K. Woźniak , M. Malinska

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.

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.

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引用次数: 0

The nature of halogen bonding: insights from interacting quantum atoms and source function studies

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252525000363

Arianna Pisati , Alessandra Forni , Stefano Pieraccini , Maurizio Sironi

Interacting quantum atoms and source function studies on a series of halogen-bonded complexes between substituted pyridines and X₂ or XCN molecules (X = I, Br) focus on the combined role played by the X and N interacting pairs and their local environment.

A detailed study of the X⋯N (X = I, Br) halogen bonds in complexes formed by an extended set of substituted pyridines with D—X molecules (D = X, 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 (i.e. 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 X⋯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.

本文报告了对一组扩展的取代吡啶与 D-X 分子（D = X，CN）形成的复合物中 X...N（X = I，Br）卤键的详细研究。通过 Bader 的分子中原子量子理论（QTAIM）和 Pendás 的量子原子相互作用（IQA）方案，在不同（MP2 和 DFT）理论水平上研究了这些相互作用的性质，重点研究了局部环境（即吡啶环上的取代基和卤化残基）对卤键特征的作用。我们发现，交换相关能对 IQA 总能的贡献很大，在某些情况下与静电项（I2 复合物）相当，甚至主导静电项（ICN 复合物）。源函数提供了有意义的信息，表明在 X...N 相互作用的键临界点上，卤原子对电子密度的贡献最大，而氮原子的贡献要小得多，它既是电子密度的源，也是电子密度的汇。此外，还确定了远端原子的相关贡献，包括吡啶环不同位置上的各种电子供体和电子吸附取代基，这凸显了电子密度的非局部性。研究人员还考察了结合能、根据 IQA 得出的相互作用能以及 QTAIM 描述因子（如析离指数和源函数）之间可能存在的关系。一般来说，只有当直接参与的卤素原子和氮原子之外的局部环境在相互作用中扮演次要角色时，才能发现良好的相关性。

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引用次数: 0

Experimental electronic structures of copper complexes with a biphenyldiimino dithioether – a model for blue copper proteins

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252524012107

Marek Fronc , Martin Breza , Lukáš Bučinský , Ingrid Jelemenská , Jozef Kožíšek

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.

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 (bite) 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 bite ligand has been adapted to the conformation required by the central atom.

引用次数: 0

A new statistical metric for robust target detection in cryo-EM using 2D template matching 基于二维模板匹配的低温电镜鲁棒目标检测新统计度量。

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252524011771

Kexin Zhang , Pilar Cossio , Aaditya V. Rangan , Bronwyn A. Lucas , Nikolaus Grigorieff

A novel statistical metric for 2D template matching (2DTM), the 2DTM p-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.

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 p-value, is developed to extend the 2DTM framework to more complex applications. The 2DTM p-value combines information from two previously used 2DTM metrics, namely the 2DTM signal-to-noise ratio (SNR) and z-score, which are derived from the cross-correlation coefficient between the target and the template. The 2DTM p-value demonstrates robust detection accuracies under various imaging and sample conditions and outperforms the 2DTM SNR and z-score alone. Specifically, the 2DTM p-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.

二维模板匹配（2D template matching, 2DTM）可用于细胞低温电镜图像中分子及其组装的检测，具有较高的位置和方向精度。虽然2DTM成功地检测了大核糖体亚基等球形靶标，但在各种环境中检测更小、更非球形靶标仍然存在挑战。在这项工作中，开发了一种新的2DTM度量，称为2DTM p值，以将2DTM框架扩展到更复杂的应用中。2DTM p值结合了之前使用的两个2DTM指标的信息，即2DTM信噪比（SNR）和z-score，它们是由目标和模板之间的相互关联系数得出的。在各种成像和样品条件下，2DTM p值显示出稳健的检测精度，并且优于单独的2DTM信噪比和z分数。具体来说，2DTM p值提高了对模拟数据中修饰的人工微管蛋白贴片颗粒（500 kDa）和更小的网格蛋白单体（193 kDa）等非球状目标的检测。即使在高斯噪声增加的条件下，该方法也能准确地恢复酵母片样中的成熟60S核糖体。新的指标将能够通过2DTM在纯化和细胞样品中检测更广泛的靶标。

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引用次数: 0

Accounting for electron-beam-induced warping of molecular nanocrystals in MicroED structure determination

IF 2.9 2区材料科学 Q2 CHEMISTRY, MULTIDISCIPLINARY

IUCrJ

Pub Date : 2025-03-01 DOI: 10.1107/S2052252524012132

Niko Vlahakis , Arden Clauss , Jose A. Rodriguez

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.

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.

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引用次数: 0

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