Evidence map›Paper›PMID 40202581›Full record

ArticleChemistry (Weinheim an der Bergstrasse, Germany)2025

Negative Cooperativity in the UHRF1 TTD-PHD Dual Domain Masks the Contributions of Cation-π Interactions between Trimethyllysine and the TTD Aromatic Cage.

Christopher R Travis, Jake R Wilkinson, Ryan G Dumais, Hanne C Henriksen, Joseph W Treacy, Noah K Schomburg, K N Houk, Marcey L Waters

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Chemistry (Weinheim an der Bergstrasse, Germany), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

8 authors.

Christopher R TravisDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.
Jake R WilkinsonDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.
Ryan G DumaisDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.
Hanne C HenriksenDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.
Joseph W TreacyDepartment of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California, 90095-1569, USA.
Noah K SchomburgDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.
K N HoukDepartment of Chemistry and Biochemistry, University of California at Los Angeles, Los Angeles, California, 90095-1569, USA.
Marcey L WatersDepartment of Chemistry, University of North Carolina at Chapel Hill, CB 3290, Chapel Hill, North Carolina, 27599, USA.ORCID https://orcid.org/0000-0002-4917-5755

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5M
Biosynthesis and Enzymology of Antifungal Natural Products - R01AI141481R01AI141481 · NIAID · UNIVERSITY OF CALIFORNIA LOS ANGELES · PI GARG, NEIL K, HOUK, KENDALL N · 2019 to 2023
$2.8M
NIH Administrative Supplement to Purchase a LyophilizerR35GM145227 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI MARCEY L WATERS · 2022 to 2026
$2.2M
Origins of Ligand Binding and Selectivity in Methyllysine Reader and Writer ProteinsR01GM118499 · NIGMS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI WATERS, MARCEY L · 2017 to 2022
$1.6M
National Cancer Institute of the National Institutes of Health P30CA016086NCI NIH HHS P30 CA016086NIAID NIH HHS R01 AI141481NIGMS NIH HHS R01 GM118499NIGMS NIH HHS R35 GM145227
6 · The paper itself

Abstract

UHRF1 is a promising epigenetic target in oncology, but inhibitor development has proven challenging due to the interplay between its tandem Tudor domain (TTD) and plant homeodomain (PHD). The TTD binds trimethyllysine (Kme3) at position 9 while the PHD binds Arg at position 2 on histone 3. Herein, we report how the PHD influences TTD recognition of the histone 3 tail containing Kme3 (H3K9me3) versus its neutral isostere, tert-butyl norleucine (tBuNle). Our findings show that the dual domain binds both peptides equally, supporting tBuNle's potential for inhibitor development. However, unexpectedly, the binding mechanism of H3K9me3 differs between the single and dual domains. In the TTD alone, Kme3 is bound in the aromatic cage via electrostatically tunable cation-π interactions, but in the dual domain, Kme3 binding is independent of electrostatics in the aromatic cage-an unprecedented observation. Computational studies suggest cation-π interactions should contribute in both cases. The contrasting experimental and computational results point to an unusual example of negative chelate cooperativity: interactions between the histone and PHD mask the mechanism of TTD recognition of K9me3. This work underscores the complexity of histone post-translational modification (PTM) readout in multi-domain proteins and demonstrates the first example of a masked cation-π interaction.

Indexed as

CCAAT-Enhancer-Binding ProteinsLysineUbiquitin-Protein LigasesBinding SitesCationsHistonesHumansProtein BindingStatic ElectricityTudor DomainCationsCCAAT-Enhancer-Binding ProteinsHistonesLysinetrimethyllysineUbiquitin-Protein LigasesUHRF1 protein, humancation‐π interactionsepigeneticsnegative cooperativitytrimethyllysine

Identifiers

PMID40202581
PMCPMC12188726

What OpenQuestion holds

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Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.