An Acetyl-Methyl Switch Drives a Conformational Change in p53

Individual posttranslational modifications (PTMs) of p53 mediate diverse p53-dependent responses, however much less is known about the combinatorial action of adjacent modifications. Here, we describe crosstalk between the early DNA damage response mark p53K382me2 and the surrounding PTMs that modulate binding of p53 co-factors, including 53BP1 and p300. The 1.8 Å resolution crystal structure of the tandem Tudor domain (TTD) of 53BP1 in complex with p53 peptide acetylated at K381 and dimethylated at K382 (p53K381acK382me2) reveals that the dual PTM induces a conformational change in p53. The α-helical fold of p53K381acK382me2 positions the side chains of R379, K381ac, and K382me2 to interact with TTD concurrently, reinforcing a modular design of double PTM mimetics. Biochemical and NMR analyses show that other surrounding PTMs, including phosphorylation of serine/threonine residues of p53, affect association with TTD. Our findings suggest a novel PTM-driven conformation switch-like mechanism that may regulate p53 interactions with binding partners

Structure Revision of Decurrensides A–E Enabled by the RFF Parametric Calculations of Proton Spin–Spin Coupling Constants

Structure revision of the recently characterized natural products, decurrensides A–E, is described. The revision is aided by fast and accurate computations of proton spin–spin coupling constants. While the 13C chemical shifts calculations could reveal the misassignment of the original structures, the calculated spin coupling constants possess much higher structural information content, informing and guiding the process of structure reassignment. Together, calculations of 13C chemical shifts and spin coupling constants constitute a robust and now practical structure discovery tool

Structure Revision of Decurrensides A–E Enabled by the <i>RFF</i> Parametric Calculations of Proton Spin–Spin Coupling Constants

Structure revision of the recently characterized natural products, decurrensides A–E, is described. The revision is aided by fast and accurate computations of proton spin–spin coupling constants. While the ¹³C chemical shifts calculations could reveal the misassignment of the original structures, the calculated spin coupling constants possess much higher structural information content, informing and guiding the process of structure reassignment. Together, calculations of ¹³C chemical shifts and spin coupling constants constitute a robust and now practical structure discovery tool

Complexity-Building ESIPT-Assisted Synthesis of Fused Polyheterocyclic Sulfonamides

Excited State Intramolecular Proton Transfer (ESIPT), originally discovered and explored in depth in a number of extensive photophysical studies, is more recently rediscovered as a powerful synthetic tool, offering rapid access to complex polyheterocycles. In our prior work we have employed ESIPT in aromatic o-keto amines and amides, leading to diverse primary photoproducts—complex quinolinols or azacanes possessing a fused lactam moiety—which could additionally be modified in short, high-yielding postphotochemical reactions to further grow complexity of the heterocyclic core scaffold and/or to decorate it with additional functional groups. Given that sulfonamides are generally known as privileged substructures, in this study we pursued two goals: (i) To explore whether sulfonamides could behave as proton donors in the context of ESIPT-initiated photoinduced reactions; (ii) To assess the scope of subsequent complexity-building photochemical and postphotochemical steps, which give access to polyheterocyclic molecular cores with fused cyclic sulfonamide moieties. In this work we show that this is indeed the case. Simple sulfonamide-containing photoprecursors produced the sought-after heterocyclic products in experimentally simple photochemical reactions accompanied by significant step-normalized complexity increases as corroborated by the Böttcher complexity scores

Computational Structure Revision of a Longipinane Derivative Meridane

Structure revision of a recently reported longipinane derivative, meridane, was enabled by computations of its NMR spectra. This structural revision necessitates corrections in the originally proposed Wagner–Meerwein mechanism for the formation of meridane