6QSC

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

Summary for 6QSC

• Entry DOI: 10.2210/pdb6qsc/pdb
• Related: 5M4G 5M4J 5MBZ
• Descriptor: Xaa-Pro dipeptidase, MANGANESE (II) ION, MANGANESE ION, 1 HYDROXYL COORDINATED, ... (7 entities in total)
• Functional Keywords: hydrolase, metal binding, dipeptidase, mutation
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 110655.00

Authors

Wilk, P.,Wator, E.,Weiss, M.S. (deposition date: 2019-02-20, release date: 2020-03-18, Last modification date: 2024-03-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.569 Å)