Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1

Ni, Xiaoling; Heidenreich, David; Christott, Thomas; Bennett, James M.; Moustakim, Moses; Brennan, P.E.; Fedorov, Oleg; Knapp, S.; Chaikuad, A.

doi:10.1101/836932

Cited by 2 publications

(2 citation statements)

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“…Peptidomimetic inhibitors and chemical probes for the AF9 YEATS domain and the closely related ENL YEATS domain that bind with nanomolar affinities have been reported, with the most potent compound replacing the alkene of the crotonyl group with an oxazole moiety 30–32 . Additionally, several groups have reported small molecule inhibitors of AF9 and ENL 33–39 . However, no inhibitor studies to date have evaluated how binding is affected when an amide is replaced with an amide isostere.…”

Section: Introductionmentioning

confidence: 99%

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Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain

et al. 2022

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AmideÀπ interactions, in which an amide interacts with an aromatic group, are ubiquitous in biology, yet remain understudied relative to other noncovalent interactions. Recently, we demonstrated that an electrostatically tunable amideÀπ interaction is key to recognition of histone acyllysine by the AF9 YEATS domain, a reader protein which has emerged as a therapeutic target due to its dysregulation in cancer. Amide isosteres are commonly employed in drug discovery, often to prevent degradation by proteases, and have proven valuable in achieving selectivity when targeting epigenetic proteins. However, like amideÀπ interactions, interactions of amide isosteres with aromatic rings have not been thoroughly studied despite widespread use. Herein, we evaluate the recognition of a series of amide isosteres by the AF9 YEATS domain using genetic code expansion to evaluate the amide isostereÀπ interaction. We show that compared to the amideÀπ interaction with the native ligand, each isostere exhibits similar electrostatic tunability with an aromatic residue in the binding pocket, demonstrating that the isosteres maintain similar interactions with the aromatic residue. We identify a urea-containing ligand that binds with enhanced affinity for the AF9 YEATS domain, offering a promising starting point for inhibitor development. Furthermore, we demonstrate that carbamate and urea isosteres of crotonyllysine are resistant to enzymatic removal by SIRT1, a protein that cleaves acyl post-translational modifications, further indicating the potential of amide isosteres in YEATS domain inhibitor development. These results also provide experimental precedent for interactions of these common drug discovery moieties with aromatic rings that can inform computational methods.

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Section: Introductionmentioning

confidence: 99%

“…[30][31][32] Additionally, several groups have reported small molecule inhibitors of AF9 and ENL. [33][34][35][36][37][38][39] However, no inhibitor studies to date have evaluated how binding is affected when an amide is replaced with an amide isostere.…”

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confidence: 99%

Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain

et al. 2022

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Urea-aromatic interactions in biology

Raghunathan

Jaganade

2020

Biophys Rev

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Noncovalent interactions are key determinants in both chemical and biological processes. Among such processes, the hydrophobic interactions play an eminent role in folding of proteins, nucleic acids, formation of membranes, protein-ligand recognition, etc.. Though this interaction is mediated through the aqueous solvent, the stability of the above biomolecules can be highly sensitive to any small external perturbations, such as temperature, pressure, pH, or even cosolvent additives, like, urea-a highly soluble small organic molecule utilized by various living organisms to regulate osmotic pressure. A plethora of detailed studies exist covering both experimental and theoretical regimes, to understand how urea modulates the stability of biological macromolecules. While experimentalists have been primarily focusing on the thermodynamic and kinetic aspects, theoretical modeling predominantly involves mechanistic information at the molecular level, calculating atomistic details applying the force field approach to the high level electronic details using the quantum mechanical methods. The review focuses mainly on examples with biological relevance, such as (1) urea-assisted protein unfolding, (2) ureaassisted RNA unfolding, (3) urea lesion interaction within damaged DNA, (4) urea conduction through membrane proteins, and (5) protein-ligand interactions those explicitly address the vitality of hydrophobic interactions involving exclusively the urea-aromatic moiety.

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Structural insights into interaction mechanisms of alternative piperazine-urea YEATS domain binders in MLLT1

Cited by 2 publications

References 37 publications

Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain

Evaluation of acyllysine isostere interactions with the aromatic pocket of the AF9 YEATS domain

Urea-aromatic interactions in biology

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