1M1D

TETRAHYMENA GCN5 WITH BOUND BISUBSTRATE ANALOG INHIBITOR

Summary for 1M1D

• Entry DOI: 10.2210/pdb1m1d/pdb
• Related: 1CMO 1QSN 1QSR 1QST 1YGH
• Descriptor: TGCN5 HISTONE ACETYL TRANSFERASE, HISTONE H3 (3 entities in total)
• Functional Keywords: histone acetyltransferase, gcn5-related n-acetyltransferase, inhibitor complex, transcription factor, transferase
• Biological source: Tetrahymena thermophila; More
• Cellular location: Nucleus: P02303
• Total number of polymer chains: 4
• Total formula weight: 44937.61

Authors

Poux, A.N.,Cebrat, M.,Kim, C.M.,Cole, P.A.,Marmorstein, R. (deposition date: 2002-06-18, release date: 2002-10-30, Last modification date: 2025-03-26)

Primary citation

Poux, A.N.,Cebrat, M.,Kim, C.M.,Cole, P.A.,Marmorstein, R.
Structure of the GCN5 histone acetyltransferase bound to a bisubstrate inhibitor.
Proc.Natl.Acad.Sci.USA, 99:14065-14070, 2002

PubMed Abstract: Histone acetyltransferases (HATs) use acetyl CoA to acetylate target lysine residues within histones and other transcription factors, such as the p53 tumor suppressor, to promote gene activation. HAT enzymes fall into subfamilies with divergence in sequence and substrate preference. Several HAT proteins have been implicated in human cancer. We have previously reported on the preparation of peptide-CoA conjugate inhibitors with distinct specificities for the p300/CBP [cAMP response element binding protein (CREB)-binding protein] or GCN5 HAT subfamilies. Here we report on the crystal structure of the GCN5 HAT bound to a peptide-CoA conjugate containing CoA covalently attached through an isopropionyl linker to Lys-14 of a 20-aa N-terminal fragment of histone H3. Surprisingly, the structure reveals that the H3 portion of the inhibitor is bound outside of the binding site for the histone substrate and that only five of the 20 aa residues of the inhibitor are ordered. Rearrangements within the C-terminal region of the GCN5 protein appear to mediate this peptide displacement. Mutational and enzymatic data support the hypothesis that the observed structure corresponds to a late catalytic intermediate. The structure also provides a structural scaffold for the design of HAT-specific inhibitors that may have therapeutic applications for the treatment of HAT-mediated cancers.

PubMed: 12391296
DOI: 10.1073/pnas.222373899

Experimental method

X-RAY DIFFRACTION (2.2 Å)