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424 a.a.
 S-adenosyl-L-methionine |
+ |
[ribulose-1,5-bisphosphate carboxylase]- lysine |
= |
 S-adenosyl-L-homocysteine |
+ |
[ribulose-1,5-bisphosphate carboxylase]-N(6)-methyl-L-lysine |
|---|
Key reference
DOI no: 10.1074/jbc.M602257200 J Biol Chem 281:19280-19287 (2006) PubMed id: 16682405
Catalytic roles for carbon-oxygen hydrogen bonding in SET domain lysine methyltransferases. J.F.Couture, G.Hauk, M.J.Thompson, G.M.Blackburn, R.C.Trievel. ABSTRACT
SET domain enzymes represent a distinct family of protein lysine methyltransferases in eukaryotes. Recent studies have yielded significant insights into the structural basis of substrate recognition and the product specificities of these enzymes. However, the mechanism by which SET domain methyltransferases catalyze the transfer of the methyl group from S-adenosyl-L-methionine to the lysine epsilon-amine has remained unresolved. To elucidate this mechanism, we have determined the structures of the plant SET domain enzyme, pea ribulose-1,5 bisphosphate carboxylase/oxygenase large subunit methyltransferase, bound to S-adenosyl-L-methionine, and its non-reactive analogs Aza-adenosyl-L-methionine and Sinefungin, and characterized the binding of these ligands to a homolog of the enzyme. The structural and biochemical data collectively reveal that S-adenosyl-L-methionine is selectively recognized through carbon-oxygen hydrogen bonds between the cofactor's methyl group and an array of structurally conserved oxygens that comprise the methyl transfer pore in the active site. Furthermore, the structure of the enzyme co-crystallized with the product epsilon-N-trimethyllysine reveals a trigonal array of carbon-oxygen interactions between the epsilon-ammonium methyl groups and the oxygens in the pore. Taken together, these results establish a central role for carbon-oxygen hydrogen bonding in aligning the cofactor's methyl group for transfer to the lysine epsilon-amine and in coordinating the methyl groups after transfer to facilitate multiple rounds of lysine methylation.
Selected figure(s)
Figure 1.
FIGURE 1. Structures of AdoMet, AdoHcy, and the cofactor analogs Sinefungin (adenosyl-L-ornithine) and AzaAdoMet.Figure 6.
FIGURE 6. Proposed catalytic role of the methyl transfer pore in the SET domain active site. The carbonyl oxygens of Ser-221 and Asp-239 and the hydroxyl group of the invariant Tyr-287 engage in CH···O hydrogen bonding with the AdoMet methyl group, aligning it for the S[N]2 transfer to the lysine-amine.
The above figures are reprinted by permission from the ASBMB: J Biol Chem (2006, 281, 19280-19287) copyright 2006. Figures were selected by an automated process.
Literature references that cite this PDB file's key reference
PubMed id Reference
20023638 J.R.Horton, A.K.Upadhyay, H.H.Qi, X.Zhang, Y.Shi, and X.Cheng (2010).
Enzymatic and structural insights for substrate specificity of a family of jumonji histone lysine demethylases.Nat Struct Mol Biol, 17, 38-43.
19194573 C.Joce, J.Caryl, P.G.Stockley, S.Warriner, and A.Nelson (2009).
Identification of stable S-adenosylmethionine (SAM) analogues derivatised with bioorthogonal tags: effect of ligands on the affinity of the E. coli methionine repressor, MetJ, for its operator DNA.Org Biomol Chem, 7, 635-638.
19263098 F.A.de Molfetta, R.F.de Freitas, A.B.da Silva, and C.A.Montanari (2009).
Docking and molecular dynamics simulation of quinone compounds with trypanocidal activity.J Mol Model, 15, 1175-1184.
19208805 S.Raunser, R.Magnani, Z.Huang, R.L.Houtz, R.C.Trievel, P.A.Penczek, and T.Walz (2009).
Rubisco in complex with Rubisco large subunit methyltransferase.Proc Natl Acad Sci U S A, 106, 3160-3165.
19219047 Y.Chang, X.Zhang, J.R.Horton, A.K.Upadhyay, A.Spannhoff, J.Liu, J.P.Snyder, M.T.Bedford, and X.Cheng (2009).
Structural basis for G9a-like protein lysine methyltransferase inhibition by BIX-01294.Nat Struct Mol Biol, 16, 312-317.
PDB code: 3fpd
19088188 J.F.Couture, L.M.Dirk, J.S.Brunzelle, R.L.Houtz, and R.C.Trievel (2008).
Structural origins for the product specificity of SET domain protein methyltransferases.Proc Natl Acad Sci U S A, 105, 20659-20664.
PDB codes: 3f9w 3f9x 3f9y 3f9z
18200608 O.Okhrimenko, and I.Jelesarov (2008).
A survey of the year 2006 literature on applications of isothermal titration calorimetry.J Mol Recognit, 21, 1.
18391193 X.Zhang, and T.C.Bruice (2008).
Enzymatic mechanism and product specificity of SET-domain protein lysine methyltransferases.Proc Natl Acad Sci U S A, 105, 5728-5732.
17517655 H.B.Guo, and H.Guo (2007).
Mechanism of histone methylation catalyzed by protein lysine methyltransferase SET7/9 and origin of product specificity.Proc Natl Acad Sci U S A, 104, 8797-8802.
17589523 J.F.Couture, E.Collazo, P.A.Ortiz-Tello, J.S.Brunzelle, and R.C.Trievel (2007).
Specificity and mechanism of JMJD2A, a trimethyllysine-specific histone demethylase.Nat Struct Mol Biol, 14, 689-695.
PDB codes: 2q8c 2q8d 2q8e The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB code is shown on the right.
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