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Crystal Structure of L-isoaspartyl (D-aspartyl) O-methyltransferase with adenosine & VYP(ISP)HA substrateCrystal Structure of L-isoaspartyl (D-aspartyl) O-methyltransferase with adenosine & VYP(ISP)HA substrate
Structural highlights
Function[PIMT_PYRFU] Catalyzes the methyl esterification of L-isoaspartyl residues in peptides and proteins that result from spontaneous decomposition of normal L-aspartyl and L-asparaginyl residues. It plays a role in the repair and/or degradation of damaged proteins (By similarity). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMedProtein L-isoaspartyl (D-aspartyl) methyltransferases (EC 2.1.1.77) are found in almost all organisms. These enzymes catalyze the S-adenosylmethionine (AdoMet)-dependent methylation of isomerized and racemized aspartyl residues in age-damaged proteins as part of an essential protein repair process. Here, we report crystal structures of the repair methyltransferase at resolutions up to 1.2 A from the hyperthermophilic archaeon Pyrococcus furiosus. Refined structures include binary complexes with the active cofactor AdoMet, its reaction product S-adenosylhomocysteine (AdoHcy), and adenosine. The enzyme places the methyl-donating cofactor in a deep, electrostatically negative pocket that is shielded from solvent. Across the multiple crystal structures visualized, the presence or absence of the methyl group on the cofactor correlates with a significant conformational change in the enzyme in a loop bordering the active site, suggesting a role for motion in catalysis or cofactor exchange. We also report the structure of a ternary complex of the enzyme with adenosine and the methyl-accepting polypeptide substrate VYP(L-isoAsp)HA at 2.1 A. The substrate binds in a narrow active site cleft with three of its residues in an extended conformation, suggesting that damaged proteins may be locally denatured during the repair process in cells. Manual and computer-based docking studies on different isomers help explain how the enzyme uses steric effects to make the critical distinction between normal L-aspartyl and age-damaged L-isoaspartyl and D-aspartyl residues. Crystal structure of a protein repair methyltransferase from Pyrococcus furiosus with its L-isoaspartyl peptide substrate.,Griffith SC, Sawaya MR, Boutz DR, Thapar N, Katz JE, Clarke S, Yeates TO J Mol Biol. 2001 Nov 9;313(5):1103-16. PMID:11700066[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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