6QSC

Crystal Structure of Arg470His mutant of Human Prolidase with Mn ions and GlyPro ligand

6QSC の概要

• エントリーDOI: 10.2210/pdb6qsc/pdb
• 関連するPDBエントリー: 5M4G 5M4J 5MBZ
• 分子名称: Xaa-Pro dipeptidase, MANGANESE (II) ION, MANGANESE ION, 1 HYDROXYL COORDINATED, ... (7 entities in total)
• 機能のキーワード: hydrolase, metal binding, dipeptidase, mutation
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 110655.00

構造登録者

Wilk, P.,Wator, E.,Weiss, M.S. (登録日: 2019-02-20, 公開日: 2020-03-18, 最終更新日: 2024-11-20)

主引用文献

Linhares, N.D.,Wilk, P.,Wator, E.,Tostes, M.A.,Weiss, M.S.,Pena, S.D.J.
Structural analysis of new compound heterozygous variants in PEPD gene identified in a patient with Prolidase Deficiency diagnosed by exome sequencing.
Genet Mol Biol, 44:e20200393-e20200393, 2021

PubMed Abstract: Prolidase Deficiency (PD) is an autosomal recessive rare disorder caused by loss or reduction of prolidase enzymatic activity due to variants in the PEPD gene. PD clinical features vary among affected individuals: skin ulcerations, recurrent infections, and developmental delay are common. In this study, we describe a 16-year-old boy with a mild PD phenotype comprising chronic eczema, recurrent infections and elevated IgE. Whole exome sequencing analysis revealed three PEPD variants: c.575T>C p.(Leu192Pro) inherited from the mother, and c.692_694del p.(Tyr231del) and c.1409G>A p.(Arg470His), both inherited from the father. The variant p.(Tyr231del) has been previously characterized by high-resolution X-ray structure analysis as altering protein dynamics/flexibility. In order to study the effects of the other two prolidase variants, we performed site directed mutagenesis purification and crystallization studies. A high-resolution X-ray structure could only be obtained for the p.(Arg470His) variant, which showed no significant structural differences in comparison to WT prolidase. On the other hand, the p.(Leu192Pro) variant led to significant protein destabilization. Hence, we conclude that the maternal p.(Leu192Pro) variant was likely causally associated with the proband´s disease, together with the known pathogenic paternal variant p.(Tyr231del). Our results demonstrated the utility of exome sequencing to perform diagnosis in PD cases with mild phenotype.

PubMed: 33877262
DOI: 10.1590/1678-4685-GMB-2020-0393

実験手法

X-RAY DIFFRACTION (1.569 Å)