3VV0

Crystal structure of histone methyltransferase SET7/9 in complex with DAAM-3

Summary for 3VV0

• Entry DOI: 10.2210/pdb3vv0/pdb
• Related: 3VUZ
• Descriptor: Histone-lysine N-methyltransferase SETD7, 5'-{[(3S)-3-amino-3-carboxypropyl][2-(hexylamino)ethyl]amino}-5'-deoxyadenosine (3 entities in total)
• Functional Keywords: set domain, transferase, adenosylmethionine binding, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Nucleus: Q8WTS6
• Total number of polymer chains: 1
• Total formula weight: 29577.83

Authors

Niwa, H.,Handa, N.,Tomabechi, Y.,Honda, K.,Toyama, M.,Ohsawa, N.,Shirouzu, M.,Kagechika, H.,Hirano, T.,Umehara, T.,Yokoyama, S. (deposition date: 2012-07-10, release date: 2013-03-27, Last modification date: 2023-11-08)

Primary citation

Niwa, H.,Handa, N.,Tomabechi, Y.,Honda, K.,Toyama, M.,Ohsawa, N.,Shirouzu, M.,Kagechika, H.,Hirano, T.,Umehara, T.,Yokoyama, S.
Structures of histone methyltransferase SET7/9 in complexes with adenosylmethionine derivatives
Acta Crystallogr.,Sect.D, 69:595-602, 2013

PubMed Abstract: SET7/9 is a protein lysine methyltransferase that methylates histone H3 and nonhistone proteins such as p53, TAF10 and oestrogen receptor α. In previous work, novel inhibitors of SET7/9 that are amine analogues of the coenzyme S-(5'-adenosyl)-L-methionine (AdoMet) have been developed. Here, crystal structures of SET7/9 are reported in complexes with two AdoMet analogues, designated DAAM-3 and AAM-1, in which an n-hexylaminoethyl group or an n-hexyl group is attached to the N atom that replaces the S atom of AdoMet, respectively. In both structures, the inhibitors bind to the coenzyme-binding site and their additional alkyl chain binds in the lysine-access channel. The N atom in the azaalkyl chain of DAAM-3 is located at almost the same position as the N-methyl C atom of the methylated lysine side chain in the substrate-peptide complex structures and stabilizes complex formation by hydrogen bonding to the substrate-binding site residues of SET7/9. On the other hand, the alkyl chain of AAM-1, which is a weaker inhibitor than DAAM-3, binds in the lysine-access channel only through hydrophobic and van der Waals interactions. Unexpectedly, the substrate-binding site of SET7/9 complexed with AAM-1 specifically interacts with the artificial N-terminal sequence of an adjacent symmetry-related molecule, presumably stabilizing the alkyl chain of AAM-1.

PubMed: 23519668
DOI: 10.1107/S0907444912052092

Experimental method

X-RAY DIFFRACTION (2.001 Å)