Investigation of P300 binding through seed-guided DE novo protein design
Active Project Grant Awarded Last action
- Award ID
- F32GM163361
- Recipient
-
Massachusetts Institute Of Technology UEI E2NYLCDML6V1
- Awarding agency
-
National Institute of General Medical Sciences
National Institutes of Health, Department of Health and Human Services
- Obligated
- $76,780
Award facts
- Assistance listing
- 93.859 Biomedical Research and Research Training
- Completion date 0% complete
- Place of performance
- Cambridge, MA 02142, USA
Award details come from USAspending.gov.
Description
- Abstract
- Innovative protein design methodologies offer unprecedented opportunities for investigating challenging protein-protein interactions. This proposal introduces a seed-guided DE novo protein design approach to study the binding interfaces of the cysteine-histidine rich domain of coactivator protein P300, a critical mediator of hypoxia-inducible gene expression in cancer. Unlike traditional approaches that primarily mimic the c-terminal transactivation domain of HIF1Α, our method leverages machine learning-identified surface-complementing fragments ( seeds ) to guide the generation of diverse protein backbones that engage multiple interfaces of P300. The primary goal is to demonstrate how seed-guided DE novo design can reveal new binding mechanisms and generate improved inhibitors compared to conventional design strategies. This research will be accomplished through three aims: (1) comparing seed-guided DE novo designs against standard rfdiffusion, hotspot-guided designs, and native-mimicking approaches using computational metrics; (2) implementing a modular high-throughput bacterial screening platform to experimentally validate and compare the effectiveness of different design strategies; and (3) biophysically characterizing top candidates to elucidate novel binding modes and mechanisms of P300 interaction. The training plan encompasses developing expertise in computational protein design workflows, bacterial screening methodologies, and biophysical characterization techniques, and considerations of therapeutic developability. This research will be conducted in professor AMY keating's laboratory at MIT, with input from collaborator prof. K. Dane wittrup, providing an exceptional training environment with expertise in protein-protein interactions, computational design tools, and high-throughput screening platforms, complemented by access to the broader resources of the MIT department of biology and the koch institute for integrative cancer research.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | -$76,780 | |
| Amendment | $76,780 | |
| Original award | $76,780 |
Quick answers
Who received award F32GM163361?
F32GM163361 was awarded to Massachusetts Institute Of Technology by National Institute of General Medical Sciences (National Institutes of Health) on November 22, 2026.
How much is award F32GM163361 worth?
$76,780 has been obligated on F32GM163361.
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