4PLC

Crystal structure of ancestral apicomplexan lactate dehydrogenase with malate.

4PLC の概要

• エントリーDOI: 10.2210/pdb4plc/pdb
• 関連するPDBエントリー: 4PLF 4PLG 4PLH 4PLT 4PLV 4PLW 4PLY 4PLZ
• 分子名称: lactate dehydrogenase, PYRUVIC ACID, 1,4-DIHYDRONICOTINAMIDE ADENINE DINUCLEOTIDE, ... (5 entities in total)
• 機能のキーワード: ancestral sequence reconstruction, dehydrogenase, apicomplexa, specificity, oxidoreductase
• 由来する生物種: Apicomplexa
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 149659.86

構造登録者

Boucher, J.I.,Jacobowitz, J.R.,Beckett, B.C.,Classen, S.,Theobald, D.L. (登録日: 2014-05-16, 公開日: 2014-07-02, 最終更新日: 2023-11-15)

主引用文献

Boucher, J.I.,Jacobowitz, J.R.,Beckett, B.C.,Classen, S.,Theobald, D.L.
An atomic-resolution view of neofunctionalization in the evolution of apicomplexan lactate dehydrogenases.
Elife, 3:e02304-e02304, 2014

PubMed Abstract: Malate and lactate dehydrogenases (MDH and LDH) are homologous, core metabolic enzymes that share a fold and catalytic mechanism yet possess strict specificity for their substrates. In the Apicomplexa, convergent evolution of an unusual LDH from MDH produced a difference in specificity exceeding 12 orders of magnitude. The mechanisms responsible for this extraordinary functional shift are currently unknown. Using ancestral protein resurrection, we find that specificity evolved in apicomplexan LDHs by classic neofunctionalization characterized by long-range epistasis, a promiscuous intermediate, and few gain-of-function mutations of large effect. In canonical MDHs and LDHs, a single residue in the active-site loop governs substrate specificity: Arg102 in MDHs and Gln102 in LDHs. During the evolution of the apicomplexan LDH, however, specificity switched via an insertion that shifted the position and identity of this 'specificity residue' to Trp107f. Residues far from the active site also determine specificity, as shown by the crystal structures of three ancestral proteins bracketing the key duplication event. This work provides an unprecedented atomic-resolution view of evolutionary trajectories creating a nascent enzymatic function.

PubMed: 24966208
DOI: 10.7554/eLife.02304

実験手法

X-RAY DIFFRACTION (1.5 Å)