2LP0: The solution structure of homeodomain-protein complex

Homeodomain-containing transcription factors play a fundamental role in the regulation of numerous developmental and cellular processes. Their multiple regulatory functions are accomplished through context-dependent inputs of target DNA sequences and collaborating protein partners. Previous studies have well established the sequence-specific DNA binding to homeodomains; however, little is known about how protein partners regulate their functions through targeting homeodomains. Here we report the solution structure of the Hox homeodomain in complex with the cell-cycle regulator, Geminin, which inhibits Hox transcriptional activity and enrolls Hox in cell proliferative control. Side-chain carboxylates of glutamates and aspartates in the C terminus of Geminin generate an overall charge pattern resembling the DNA phosphate backbone. These residues provide electrostatic interactions with homeodomain, which combine with the van der Waals contacts to form the stereospecific complex. We further showed that the interaction with Geminin is homeodomain subclass-selective and Hox paralog-specific, which relies on the stapling role of residues R43 and M54 in helix III and the basic amino acid cluster in the N terminus. Interestingly, we found that the C-terminal residue Ser184 of Geminin could be phosphorylated by Casein kinase II, resulting in the enhanced binding to Hox and more potent inhibitory effect on Hox transcriptional activity, indicating an additional layer of regulation. This structure provides insight into the molecular mechanism underlying homeodomain-protein recognition and may serve as a paradigm for interactions between homeodomains and DNA-competitive peptide inhibitors.
PDB ID: 2LP0Download
MMDB ID: 100218
PDB Deposition Date: 2012/1/29
Updated in MMDB: 2012/06
Experimental Method:
solution nmr
Source Organism:
Similar Structures:
Biological Unit for 2LP0: dimeric; determined by author
Molecular Components in 2LP0
Label Count Molecule
Proteins (2 molecules)
Homeobox Protein Hox-c9(Gene symbol: HOXC9)
Molecule annotation
Geminin(Gene symbol: GMNN)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB