Refinement of multiconformer ensemble models from multi-temperature X-ray diffraction data

Du, Siyuan; Wankowicz, Stephanie A.; Yabukarski, Filip; Doukov, Tzanko; Herschlag, Daniel; Fraser, James S.

doi:10.1016/bs.mie.2023.06.009

Cited by 4 publications

(8 citation statements)

References 85 publications

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“…Recent reviews discuss the experimental methods that provide structural information on multiple conformational states of biomolecules [26][27][28]. Crystallographic studies, using either X-ray or neutron diffraction, may capture different states in different crystal forms.…”

Section: Experimental Methods For Characterizing Multiple Conformatio...mentioning

confidence: 99%

“…Electron density can also often be fit to multiple conformations within a single crystal. Room-temperature (or higher temperature) X-ray crystallography may avoid structural bias from cryogenic cooling and reveal motions crucial for catalysis, ligand binding, and allosteric regulation [12,[28][29][30]. Other experimental data types, such as small-angle Xray scattering (SAXS) [27] and electron microscopy (cryoEM) [31][32][33] data, can frequently only be fit to multi-conformer models.…”

Section: Experimental Methods For Characterizing Multiple Conformatio...mentioning

confidence: 99%

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Representing structures of the multiple conformational states of proteins

Ramelot,

Tejero,

Montelione

2023

Preprint

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Biomolecules exhibit dynamic behavior that single-state models of their structures cannot fully capture. We review some recent advances for investigating multiple conformations of biomolecules, including experimental methods, molecular dynamics simulations, and machine learning. We also address the challenges associated with representing single- and multiple-state models in data archives, with a particular focus on NMR structures. Establishing standardized representations and annotations will facilitate effective communication and understanding of these complex models to the broader scientific community.

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Section: Experimental Methods For Characterizing Multiple Conformatio...mentioning

confidence: 99%

Section: Experimental Methods For Characterizing Multiple Conformatio...mentioning

confidence: 99%

Representing structures of the multiple conformational states of proteins

Ramelot,

Tejero,

Montelione

2023

Preprint

View full text Add to dashboard Cite

show abstract

“… 28–31 Combined with experimentally derived or predicted atomic models, integrative SAXS models can offer impressively comprehensive views of macromolecular states and dynamics. 24,32 …”

Section: Introductionmentioning

confidence: 99%

Identifying protein conformational states in the Protein Data Bank: Toward unlocking the potential of integrative dynamics studies

Ellaway,

Anyango,

Nair

et al. 2024

Structural Dynamics

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Studying protein dynamics and conformational heterogeneity is crucial for understanding biomolecular systems and treating disease. Despite the deposition of over 215 000 macromolecular structures in the Protein Data Bank and the advent of AI-based structure prediction tools such as AlphaFold2, RoseTTAFold, and ESMFold, static representations are typically produced, which fail to fully capture macromolecular motion. Here, we discuss the importance of integrating experimental structures with computational clustering to explore the conformational landscapes that manifest protein function. We describe the method developed by the Protein Data Bank in Europe – Knowledge Base to identify distinct conformational states, demonstrate the resource's primary use cases, through examples, and discuss the need for further efforts to annotate protein conformations with functional information. Such initiatives will be crucial in unlocking the potential of protein dynamics data, expediting drug discovery research, and deepening our understanding of macromolecular mechanisms.

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“…Exploiting temperature-controlled X-ray crystallography to capture proteins in action is therefore essential to providing the atomic level snapshots that most accurately resemble the conformational ensembles measured in solution, including sparsely-populated intermediates that are otherwise invisible, which in allosteric systems can represent “pseudo-active” states ( Weik and Colletier, 2010 ). Capturing such states by sampling at variable temperature can elucidate the vastness of conformational changes in a given system ( Du et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

“…Current approaches to collecting X-ray diffraction data above room temperature must circumvent radiation damage by limiting initial testing exposures, reducing X-ray dosage and exposure time, or utilizing novel materials as sample holders ( Roedig et al, 2015 ; Dou et al, 2020 ). Such strategies were leveraged in the study of proteinase K by Fraser and coworkers, enabling X-ray diffraction to be collected at 313K, 333K, 343K, 353K, and 363 K. The resulting models of alternative backbone and side chain conformations, as well as extensive and disparate conformational changes across the temperature range (including the elucidation of previously invisible ligand binding site, Figure 2 ), illustrates the power of time and temperature resolution in X-ray crystallography ( Du et al, 2023 ).…”

Section: Introductionmentioning

confidence: 99%

Temperature as a modulator of allosteric motions and crosstalk in mesophilic and thermophilic enzymes

Knight,

Widjaja,

Lisi

2023

Front. Mol. Biosci.

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Mesophilic and thermophilic enzyme counterparts are often studied to understand how proteins function under harsh conditions. To function well outside of standard temperature ranges, thermophiles often tightly regulate their structural ensemble through intra-protein communication (via allostery) and altered interactions with ligands. It has also become apparent in recent years that the enhancement or diminution of allosteric crosstalk can be temperature-dependent and distinguish thermophilic enzymes from their mesophilic paralogs. Since most studies of allostery utilize chemical modifications from pH, mutations, or ligands, the impact of temperature on allosteric function is comparatively understudied. Here, we discuss the biophysical methods, as well as critical case studies, that dissect temperature-dependent function of mesophilic-thermophilic enzyme pairs and their allosteric regulation across a range of temperatures.

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Refinement of multiconformer ensemble models from multi-temperature X-ray diffraction data

Cited by 4 publications

References 85 publications

Representing structures of the multiple conformational states of proteins

Representing structures of the multiple conformational states of proteins

Identifying protein conformational states in the Protein Data Bank: Toward unlocking the potential of integrative dynamics studies

Temperature as a modulator of allosteric motions and crosstalk in mesophilic and thermophilic enzymes

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