# Targeting the ET domain of BET proteins: specificity and selectivity

> **NIH NIH R01** · UNIVERSITY OF FLORIDA · 2023 · $304,965

## Abstract

Project Summary
BET proteins are directly involved in pathologies such as viral infection and different types of
cancer. Although the different BET proteins satisfy different roles in the cell and are preferentially
expressed in different tissues, current BET inhibition strategies are non-specific – resulting in
toxicity. The ET domain of BET proteins has recently emerged as a protein interaction hub with
promising selectivity of binders towards specific BET proteins – making the ET domain an
interesting target towards the design of novel drug therapeutics. Yet, little is known about the ET
interactome or its binding mechanism. This proposal aims to increase our understanding of the
ET interactome (Aim 1) by using computational tools to: a) identify possible binders; b) select the
strongest binders using machine learning and physics-based approaches; and c) characterize the
most promising leads through NMR experiments. The challenge lies in addressing the
polymorphic nature of ET: it can undergo conformational changes to bind different peptide
sequences – which in turn bind along different binding modes. Such binding plasticity
concomitantly leads to a wide range of binding affinities. Furthermore, a particular peptide
sequence binds the ET domain of different BET proteins with different binding affinities, setting
the foundation for the design of inhibitors specific to each BET protein. However, it is not clear
where the origin of specificity lies, as the ET domains have high sequence and structural similarity
across BET members. Thus, Aim 2 will unveil the binding mechanism for peptides to ET and
elucidate the origin of specificity through the use of adaptive sampling molecular dynamics
strategies and Markov State Models. The relationship between binding affinity and binding mode
is currently unknown. It could be that virus are exploiting a binding mode that leads to higher
binding affinity than those used by regulatory host proteins. Aim 3 of the proposal addresses this
issue by designing novel peptide binders to identify the limits of binding affinity amongst the
different binding modes. These computational designs will lead to the identification of hot-spot
regions in the binding domain to exploit towards the long-term goal of therapeutic design
strategies.

## Key facts

- **NIH application ID:** 10637266
- **Project number:** 1R01GM149646-01
- **Recipient organization:** UNIVERSITY OF FLORIDA
- **Principal Investigator:** Alberto Perez
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $304,965
- **Award type:** 1
- **Project period:** 2023-06-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10637266

## Citation

> US National Institutes of Health, RePORTER application 10637266, Targeting the ET domain of BET proteins: specificity and selectivity (1R01GM149646-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10637266. Licensed CC0.

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