Saturday, July 5, 2025 7/5/2025

Structural insights into the Argonaute-containing CDK8 complex

Award Number: R01GM143587
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

Group Awards By:

View Award Description

Structural insights into the Argonaute-containing CDK8 complex - Abstract In eukaryotes, transcription Mediator contains a dissociable Cdk8 kinase module (CKM) that regulates gene expression through kinase-dependent and -independent functions. The human CKM consists of Med13, Med12, Cdk8, and CycC subunits, which are either mutated or amplified in neurodevelopmental disorders and multiple cancers, such as breast and colorectal cancers. Despite extensive links between CKM and human diseases, the fundamental mechanisms of CKM in regulation of gene transcription remain poorly understood. The long-term goal is to elucidate the molecular mechanisms by which CKM regulates gene transcription through its kinase function and nucleic acid interactions. The overall objectives in this application are to (i) reveal the structure basis and functional roles of CKM subunits, (ii) elucidate the activation mechanism of Cdk8 and the way in which it recognizes substrates for phosphorylation, and (iii) investigate the functional interactions between Med13 and nucleic acids. Three aims are proposed in this application. Aim 1 is to uncover the high-resolution structure of yeast CKM and understand how Cdk8 becomes activated by Med12 and binds substrates. We will use single-particle cryo-EM to reveal interactions how the targets the overall structure of yeast CKM and its with Cdk8 substrates. We will use biochemical approaches to elucidate the detailed mechanism of Cdk8 kinase is activated by Med12 through a non-canonical mechanism. In Aim 2 , we will characterize nucleic acid binding properties of Med13 using biochemical approaches as well as identify its binding using next-generation sequencing. In Aim 3, we willuse our detailed knowledge of yCKM to reinforce our knowledge gained from studies of human CKM's structure, substrate binding, and disease mutations. proposed kinase regulation The studies are significant because they will provide valuable structural and functional insights into the function and nucleic acids interaction of CKM revealing the fundamental mechanisms of CKM in of gene expression. Ultimately, our results will offer , a structural foundation for development of kinase inhibitors to treat Cdk8-driven human diseases.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $337,116 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	4	7/29/2024	NON-COMPETING CONTINUATION	$337,116
														Subtotal = $337,116

Issue Date FY: 2023 ( Subtotal = $337,116 )
2023	2023	UNIVERSITY OF HEALTH SCIENCE CENTER	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	3	9/6/2023	NON-COMPETING CONTINUATION	$337,116
														Subtotal = $337,116

Issue Date FY: 2022 ( Subtotal = $337,116 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	2	7/13/2022	NON-COMPETING CONTINUATION	$337,116
														Subtotal = $337,116

Issue Date FY: 2021 ( Subtotal = $337,116 )
2021	2021	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON, THE	7000 FANNIN ST	HOUSTON	TX	77030	HARRIS	USA	Biomedical Research and Research Training	000	1	7/23/2021	NEW	$337,116
														Subtotal = $337,116

Grand Total All Awards = $1,348,464

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Structural insights into the Argonaute-containing CDK8 complex

Award Number: R01GM143587

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer