PDBsum entry: 3cbm

Transferase/transferase receptor

PDB id: 3cbm

Contents

Protein chain

243 a.a. *

Ligands

ILE-LYS-ARG-SER-MLZ-LYS-ASN

SAH

BME ×3

Waters ×155

* Residue conservation analysis

PDB id:

3cbm

Name:

Transferase/transferase receptor

Title:

Set7/9-er-adomet complex

Structure:

Histone-lysine n-methyltransferase setd7. Chain: a. Fragment: unp residues 111-366. Synonym: histone h3-k4 methyltransferase setd7, h3-k4- hmtase setd7, set domain-containing protein 7, set7/9, lysine n-methyltransferase 7. Engineered: yes. Estrogen receptor. Chain: b.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: setd7, kiaa1717, kmt7, set7, set9. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Other_details: er peptide

Resolution:

1.69Å R-factor: 0.196 R-free: 0.229

Authors:

X.Cheng,D.Jia

Key ref:

K.Subramanian et al. (2008). Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase. Mol Cell, 30, 336-347. PubMed id: 18471979 DOI: 10.1016/j.molcel.2008.03.022

Date:

22-Feb-08 Release date: 13-May-08

Protein chain

Q8WTS6  (SETD7_HUMAN) -  Histone-lysine N-methyltransferase SETD7

Seq: 366 a.a.

Struc: 243 a.a.

Enzyme reactions

• Enzyme class: E.C.2.1.1.43 - Histone-lysine N-methyltransferase.
• Reaction: S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine + N₆-methyl-L-lysine-[histone]

S-adenosyl-L-methionine + L-lysine-[histone] = S-adenosyl-L-homocysteine (Bound ligand (Het Group name = SAH) corresponds exactly) + N(6)-methyl-L-lysine-[histone]

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

DOI no: 10.1016/j.molcel.2008.03.022

Mol Cell 30:336-347 (2008)

PubMed id: 18471979

Regulation of estrogen receptor alpha by the SET7 lysine methyltransferase.

K.Subramanian, D.Jia, P.Kapoor-Vazirani, D.R.Powell, R.E.Collins, D.Sharma, J.Peng, X.Cheng, P.M.Vertino.

ABSTRACT

Estrogen receptor alpha (ER) is a ligand-dependent transcription factor. Upon binding estrogen, ER recruits coactivator complexes with histone acetyltransferase or methyltransferase activities to activate downstream target genes. In addition to histones, coactivators can modify ER itself and other proteins in the transactivation complex. Here, we show that ER is directly methylated at lysine 302 (K302) by the SET7 methyltransferase. SET7-mediated methylation stabilizes ER and is necessary for the efficient recruitment of ER to its target genes and for their transactivation. The SET7-ER complex structure reveals the molecular basis for ER peptide recognition and predicts that modifications or mutations of nearby residues would affect K302 methylation. Indeed, a breast cancer-associated mutation at K303 (K303R) alters methylation at K302 in vitro and in vivo. These findings raise the possibility that generation, recognition, and removal of modifications within the ER hinge region generate "ER modification cassettes" that yield distinct patterns for signaling downstream events.

Selected figure(s)

Figure 2.
Figure 2. ER Is Methylated In Vivo
(A) HeLa cells were transfected with expression constructs for Myc-SET7 and wild-type (WT) or mutant (K302R, K303R) ER, or a vector control (−). (Top) After 48 hr, ER was immunoprecipitated from 1 mg protein lysate using an anti-ER antibody and analyzed by western blotting with anti-ER K302me1 or anti-ER antibodies. (Bottom) One-tenth of input was analyzed by western blotting with the indicated antibodies.
(B) MCF7 cells were transfected with expression constructs for Myc-SET7 and wild-type (WT) or mutant (K302R) ER or vector (−). (Upper left) After 48 hr, total ER was immunoprecipitated from 1 mg protein lysates by using an anti-ER antibody and analyzed by western blot with the anti-ER K302me1 or anti-ER antibodies. (Upper right) The same protein lysates (1 mg) used in lanes 5 and 7 were immunoprecipitated with the anti-ER K302me1 antibody and analyzed by western blot with an anti-ER antibody. (Bottom) One-tenth of input was analyzed by western blot with the indicated antibodies.

Figure 6.
Figure 6. Structure of the ER-SET7 Complex
(A) The reaction occurred during crystallization, the methyl group has transferred to the epsilon -amino of ER-K302, and AdoMet is converted to AdoHcy, which is still present in the complex (right panel). The AdoMet analog sinefungin (adenosyl ornithine) was used to prepare a ternary complex mimicking the step prior to methyl transfer because it also carries a formal positive charge on the epsilon amino group (middle panel). The substrate peptide and sinefungin, or the methlyated peptide and the reaction product AdoHcy, are located at the opposite ends of the target lysine-binding channel. The atoms are colored as follows: red, nitrogen; blue, oxygen; gray, carbon; and yellow, sulfur.
(B) Three pairs of salt bridges and hydrogen bonds define SET7-ER-peptide interactions (dashed lines). Inset is a surface representation of the peptide-binding groove.

The above figures are reprinted from an Open Access publication published by Cell Press: Mol Cell (2008, 30, 336-347) copyright 2008.

Figures were selected by the author.