1YR2

Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Inter-Domain Dynamics in Catalysis and Specificity

1YR2 の概要

• エントリーDOI: 10.2210/pdb1yr2/pdb
• 分子名称: prolyl oligopeptidase, GLYCEROL (3 entities in total)
• 機能のキーワード: prolyl endopeptidase, mechanistic study, celiac sprue, hydrolase
• 由来する生物種: Novosphingobium capsulatum
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 80841.91

構造登録者

Shan, L.,Mathews, I.I.,Khosla, C. (登録日: 2005-02-02, 公開日: 2005-03-15, 最終更新日: 2023-08-23)

主引用文献

Shan, L.,Mathews, I.I.,Khosla, C.
Structural and Mechanistic Analysis of Two Prolyl Endopeptidases: Role of Interdomain Dynamics in Catalysis and Specificity
Proc.Natl.Acad.Sci.USA, 102:3599-3604, 2005

PubMed Abstract: Prolyl endopeptidases (PEPs) are a unique class of serine proteases with considerable therapeutic potential for the treatment of celiac sprue. The crystal structures of two didomain PEPs have been solved in alternative configurations, thereby providing insights into the mode of action of these enzymes. The structure of the Sphingomonas capsulata PEP, solved and refined to 1.8-A resolution, revealed an open configuration of the active site. In contrast, the inhibitor-bound PEP from Myxococcus xanthus was crystallized (1.5-A resolution) in a closed form. Comparative analysis of the two structures highlights a critical role for the domain interface in regulating interdomain dynamics and substrate specificity. Structure-based mutagenesis of the M. xanthus PEP confirms an important role for several interfacial residues. A salt bridge between Arg-572 and Asp-196/Glu-197 appears to act as a latch for opening or closing the didomain enzyme, and Arg-572 and Ile-575 may also help secure the incoming peptide substrate to the open form of the enzyme. Arg-618 and Asp-145 are responsible for anchoring the invariant proline residue in the active site of this postproline-cleaving enzyme. A model is proposed for the docking of a representative substrate PQPQLPYPQPQLP in the active site, where the N-terminal substrate residues interact extensively with the catalytic domain, and the C-terminal residues stretch into the propeller domain. Given the promise of the M. xanthus PEP as an oral therapeutic enzyme for treating celiac sprue, our results provide a strong foundation for further optimization of the PEP's clinically useful features.

PubMed: 15738423
DOI: 10.1073/pnas.0408286102

実験手法

X-RAY DIFFRACTION (1.8 Å)