3S9G

Structure of human Hexim1 (delta stammer) coiled coil domain

Summary for 3S9G

• Entry DOI: 10.2210/pdb3s9g/pdb
• Related: 2GD7
• Descriptor: Protein HEXIM1 (2 entities in total)
• Functional Keywords: cyclin t-binding domain (tbd), cyclin t1/p-tefb/7sk snrna, nucleus, transcription
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: O94992
• Total number of polymer chains: 2
• Total formula weight: 24841.53

Authors

Bigalke, J.M.,Blankenfeldt, W.,Geyer, M. (deposition date: 2011-06-01, release date: 2011-10-19, Last modification date: 2024-02-28)

Primary citation

Bigalke, J.M.,Dames, S.A.,Blankenfeldt, W.,Grzesiek, S.,Geyer, M.
Structure and Dynamics of a Stabilized Coiled-Coil Domain in the P-TEFb Regulator Hexim1.
J.Mol.Biol., 414:639-653, 2011

PubMed Abstract: The positive transcription elongation factor P-TEFb mediates the transition from transcription initiation to productive elongation by phosphorylation of the C-terminal domain of RNA polymerase II. P-TEFb is negatively regulated by the cellular protein Hexim1 (hexamethylene bisacetamide-inducible protein 1), which is highly conserved in higher eukaryotes. The C-terminal coiled-coil domain of Hexim1 recognizes the Cyclin T subunit of P-TEFb, whereas a central PYNT motif is required to inhibit the cyclin-dependent kinase Cdk9 by a yet unknown mechanism. Here, the crystal structure of the Cyclin T-binding domain (TBD) of human Hexim1 was determined at 2.1 Å resolution using a deletion mutant of three residues in its central stammer motif. The structure showed a continuous parallel coiled-coil domain of nine hepta-repeats with a preceding helix encompassing up to 15 residues. Two uncommon residues at heptad a positions in the N-terminal part of the coiled-coil structure, Lys284 and Tyr291, stabilize the preceding helix by a tight intermolecular hydrogen bond network with residues of the opposing chain. These interactions delineate a characteristic turn between both helices that is supposed to mediate binding to Cyclin T1. Stabilization of the coiled-coil domain by deletion of the stammer region was confirmed by NMR spectroscopic and backbone dynamic analyses analyzing wild-type TBD and three mutant variants. This study thus provides structural insights into the recognition of the regulator protein Hexim1 by P-TEFb and the modulation of coiled-coil dynamics by specific discontinuities.

PubMed: 22033481
DOI: 10.1016/j.jmb.2011.10.022

Experimental method

X-RAY DIFFRACTION (2.1 Å)