Methyllysine binding domains: Structural insight and small molecule probe development

Teske, Kelly A.; Hadden, M. Kyle

doi:10.1016/j.ejmech.2017.04.047

Cited by 30 publications

(44 citation statements)

References 170 publications

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“…[1][2] This large family of proteins consists of Chromo, PHD, Tudor, MBT and PWWP domains. 3 Within the Tudor domains, there are five human spindlin proteins (SPIN1, 2A, 2B, 3 and 4) and each contain three Tudor methyl reader domains. [4][5][6][7][8][9] Spindlin1 (SPIN1) was initially identified in mouse oocytes, 4 but has now been implicated in many cancers.…”

Section: Introductionmentioning

confidence: 99%

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function

et al. 2019

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Modifications of histone tails, including lysine/arginine methylation, provide the basis of a 'chromatin or histone code'. Proteins that contain 'reader' domains can bind to these modifications and form specific effector complexes, which ultimately mediate chromatin function. The spindlin1 (SPIN1) protein contains three Tudor methyllysine/arginine reader domains and was identified as a putative oncogene and transcriptional co-activator. Here we report a SPIN1 chemical probe inhibitor with low nanomolar in vitro activity, exquisite selectivity on a panel of methyl reader and writer proteins, and with submicromolar cellular activity. X-ray crystallography showed that this Tudor domain chemical probe simultaneously engages Tudor domains 1 and 2 via a bidentate binding mode. Small molecule inhibition and siRNA knockdown of SPIN1, as well as chemoproteomic studies, identified genes which are transcriptionally regulated by SPIN1 in squamous cell carcinoma and suggest that SPIN1 may have a roll in cancer related inflammation and/or cancer metastasis. a n ≥ 2. Abbreviations; BLI (BioLayer Interferometry), ITC (Isothermal Titration Calorimetry), nd (not determined).

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Section: Introductionmentioning

confidence: 99%

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function

et al. 2019

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“…The aromatic cage presents an electronrich yet hydrophobic surface that is ideally suited to bind methylated lysines through cation-π interactions [18]. The structural features and similarities, as well as their substrate specificity, have been subject to literature reviews [19][20][21].…”

Section: Nucleosome-binding Epitopesmentioning

confidence: 99%

Recognition of Nucleosomes by Chromatin Factors: Lessons from Data-Driven Docking-Based Structures of Nucleosome-Protein Complexes

Horn¹,

Ingen²

2020

Chromatin and Epigenetics

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The function of chromatin ultimately depends on the many chromatin-associated proteins and protein complexes that regulate all DNA-templated processes such as transcription, repair and replication. As the molecular docking platform for these proteins, the nucleosome is the essential gatekeeper to the genome. As such, the nucleosome-binding activity of a myriad of proteins is essential for a healthy cell. Here, we review the molecular basis of nucleosome-protein interactions and classify the different binding modes available. The structural data needed for such studies not only come from traditional sources such as X-Ray crystallography but also increasingly from other sources. In particular, we highlight how partial interaction data, derived from for example NMR or mutagenesis, are used in data-driven docking to drive the modeling of the complex into an atomistic structure. This approach has opened up detailed insights for several nucleosome-protein complexes that were intractable or recalcitrant to traditional methods. These structures guide the formation of new hypotheses and advance our understanding of chromatin function at the molecular level.

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“…Histone lysine residues mono-, di-, or trimethylated at the ε-amino position are some of the most common chromatin PTMs. The Kme reader proteins that recognize these modifications can be grouped into four general families identified as Ankyrin repeats, WD-40 repeat domains, plant homeodomain (PHD) fingers, and Royal family proteins [10]. A general characteristic of Kme readers is the formation of a binding pocket cage made of 2-4 aromatic residues, which coordinates the modified residue [11].…”

Section: Introductionmentioning

confidence: 99%

“…Several features of the Kme reader proteins make this an attractive target class family for small molecule and/or peptidomimetic inhibitor discovery [10,11,13,14]: 1) there are over 200 Kme readers present in the human proteome; 2) each domain contains a shared common binding motif; 3) structural insight exists on how to potentially gain selectivity; and 4) misregulation of Kme proteins is associated with several diseases. Target class drug discovery is a systematic strategy that utilizes established knowledge in chemistry, biology, and structural biology to leverage and rationalize plans for discovering new, selective inhibitors.…”

Section: Introductionmentioning

confidence: 99%

Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins

et al. 2020

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Chromatin structure and function, and consequently cellular phenotype, is regulated in part by a network of chromatin-modifying enzymes that place post-translational modifications (PTMs) on histone tails. These marks serve as recruitment sites for other chromatin regulatory complexes that ‘read’ these PTMs. High-quality chemical probes that can block reader functions of proteins involved in chromatin regulation are important tools to improve our understanding of pathways involved in chromatin dynamics. Insight into the intricate system of chromatin PTMs and their context within the epigenome is also therapeutically important as misregulation of this complex system is implicated in numerous human diseases. Using computational methods, along with structure-based knowledge, we have designed and constructed a focused DNA-Encoded Library (DEL) containing approximately 60,000 compounds targeting bi-valent methyl-lysine (Kme) reader domains. Additionally, we have constructed DNA-barcoded control compounds to allow optimization of selection conditions using a model Kme reader domain. We anticipate that this target-class focused approach will serve as a new method for rapid discovery of inhibitors for multivalent chromatin reader domains.

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Methyllysine binding domains: Structural insight and small molecule probe development

Cited by 30 publications

References 170 publications

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function

A Chemical Probe for Tudor Domain Protein Spindlin1 to Investigate Chromatin Function

Recognition of Nucleosomes by Chromatin Factors: Lessons from Data-Driven Docking-Based Structures of Nucleosome-Protein Complexes

Design and Construction of a Focused DNA-Encoded Library for Multivalent Chromatin Reader Proteins

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