Fragment-Based Discovery of AF9 YEATS Domain Inhibitors

Liu, Yaqian; Jin, Ruo-Xing; Lü, Hui; Bian, Kang‐Jie; Wang, Rui; Wang, Lei; Gao, Rui; Zhang, Jiahai; Wu, Jihui; Yao, Xuebiao; Liu, Xing; Liú, Dan; Wang, Xisheng; Zhang, Zhiyong; Ruan, Ke

doi:10.3390/ijms23073893

Cited by 6 publications

(4 citation statements)

References 45 publications

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“…In summary, our study sheds new light on chromatin regulation as a possible therapeutic target in fungal infections by exploring the potential of the YEATS domain readers, which are being explored for inhibitor development for cancer treatments ( 20 – 27 ). Our studies with C. albicans Yaf9 (this study) and Taf14 ( 28 ) argue that, in contrast to cancer cells, the inhibition of the YEATS domain would not be efficacious against this pathogen.…”

Section: Discussionmentioning

confidence: 98%

“…The YEATS domain recognizes crotonylated and acetylated histone lysines ( 14 – 18 ) and is found in several proteins that possess DNA transcription and repair functions ( 19 ). Since mammalian YEATS proteins are involved in cancerous transformations, YEATS domain inhibitors are attractive as a possible treatment of some cancers ( 20 – 27 ). The YEATS domain is found across fungal species ( 28 ), and the evidence for the importance of YEATS proteins in fungal virulence is building.…”

Section: Introductionmentioning

confidence: 99%

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The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Lo,

Wang,

Nickson

et al. 2024

mSphere

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Fungal infections cause a large health burden but are treated by only a handful of antifungal drug classes. Chromatin factors have emerged as possible targets for new antifungals. These targets include the reader proteins, which interact with posttranslationally modified histones to influence DNA transcription and repair. The YEATS domain is one such reader recognizing both crotonylated and acetylated histones. Here, we performed a detailed structure/function analysis of the Candida albicans YEATS domain reader Yaf9, a subunit of the NuA4 histone acetyltransferase and the SWR1 chromatin remodeling complex. We have previously demonstrated that the homozygous deletion mutant yaf9Δ/Δ displays growth defects and is avirulent in mice. Here we show that a YEATS domain mutant expected to inactivate Yaf9’s chromatin binding does not display strong phenotypes in vitro , nor during infection of immune cells or in a mouse systemic infection model, with only a minor virulence reduction in vivo . In contrast to the YEATS domain mutation, deletion of the C-terminal domain of Yaf9, a protein–protein interaction module necessary for its interactions with SWR1 and NuA4, phenocopies the null mutant. This shows that the C-terminal domain is essential for Yaf9 roles in vitro and in vivo , including C. albicans virulence. Our study informs on the strategies for therapeutic targeting of Yaf9, showing that approaches taken for the mammalian YEATS domains by disrupting their chromatin binding might not be effective in C. albicans , and provides a foundation for studying YEATS proteins in human fungal pathogens. IMPORTANCE The scarcity of available antifungal drugs and rising resistance demand the development of therapies with new modes of action. In this context, chromatin regulation may be a target for novel antifungal therapeutics. To realize this potential, we must better understand the roles of chromatin regulators in fungal pathogens. Toward this goal, here, we studied the YEATS domain chromatin reader Yaf9 in Candida albicans . Yaf9 uses the YEATS domain for chromatin binding and a C-terminal domain to interact with chromatin remodeling complexes. By constructing mutants in these domains and characterizing their phenotypes, our data indicate that the Yaf9 YEATS domain might not be a suitable therapeutic drug target. Instead, the Yaf9 C-terminal domain is critical for C. albicans virulence. Collectively, our study informs how a class of chromatin regulators performs their cellular and pathogenesis roles in C. albicans and reveals strategies to inhibit them.

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Section: Discussionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Lo,

Wang,

Nickson

et al. 2024

mSphere

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“…Several protein structural domains are known to have the ability to recognize or ‘read’ acetylated lysine residues precisely. These include the bromodomains, YEATS domains, and double plant homeodomain (PHD) finger domains, with the bromodomain being the most extensively studied [ 83 , 84 , 85 , 86 ]. Genome-wide histone acetylation has been shown to enhance correlations between transcriptional regulatory regions or between these regions and transcriptional activators.…”

Section: Histone Acetylationmentioning

confidence: 99%

Role of Histone Modifications in Kidney Fibrosis

Pan,

Yuan,

Xia

et al. 2024

Medicina

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Chronic kidney disease (CKD) is characterized by persistent kidney dysfunction, ultimately resulting in end-stage renal disease (ESRD). Renal fibrosis is a crucial pathological feature of CKD and ESRD. However, there is no effective treatment for this condition. Despite the complex molecular mechanisms involved in renal fibrosis, increasing evidence highlights the crucial role of histone modification in its regulation. The reversibility of histone modifications offers promising avenues for therapeutic strategies to block or reverse renal fibrosis. Therefore, a comprehensive understanding of the regulatory implications of histone modifications in fibrosis may provide novel insights into more effective and safer therapeutic approaches. This review highlights the regulatory mechanisms and recent advances in histone modifications in renal fibrosis, particularly histone methylation and histone acetylation. The aim is to explore the potential of histone modifications as targets for treating renal fibrosis.

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“…The terminal methyl group of Kcr is apparently recognised by a CH-π mediated contact with the Phe28 residue of AF9 YEATS ( Figure 1 B,C) [ 17 , 21 ]. Due to its biomedical importance, peptidomimetic and small molecule inhibitors of AF9 YEATS have been developed by targeting the π-π-π stacking interaction at the Kcr recognition site [ 22 , 23 , 24 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Recognition of Methacryllysine and Crotonyllysine by the AF9 YEATS Domain

Bilgin

Moesgaard

Rahman

et al. 2023

IJMS

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Histone lysine methacrylation and crotonylation are epigenetic marks that play important roles in human gene regulation. Here, we explore the molecular recognition of histone H3 peptides possessing methacryllysine and crotonyllysine at positions 18 and 9 (H3K18 and H3K9) by the AF9 YEATS domain. Our binding studies demonstrate that the AF9 YEATS domain displays a higher binding affinity for histones possessing crotonyllysine than the isomeric methacryllysine, indicating that AF9 YEATS distinguishes between the two regioisomers. Molecular dynamics simulations reveal that the crotonyllysine/methacryllysine-mediated desolvation of the AF9 YEATS domain provides an important contribution to the recognition of both epigenetic marks. These results provide important knowledge for the development of AF9 YEATS inhibitors, an area of biomedical interest.

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Fragment-Based Discovery of AF9 YEATS Domain Inhibitors

Cited by 6 publications

References 45 publications

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

The C-terminal protein interaction domain of the chromatin reader Yaf9 is critical for pathogenesis of Candida albicans

Role of Histone Modifications in Kidney Fibrosis

Molecular Recognition of Methacryllysine and Crotonyllysine by the AF9 YEATS Domain

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