Crystal and EM structures of human phosphoribosyl pyrophosphate synthase I (PRS1) provide novel insights into the disease-associated mutations

PloS One
Peng ChenXu Li

Abstract

Human PRS1, which is indispensable for the biosynthesis of nucleotides, deoxynucleotides and their derivatives, is associated directly with multiple human diseases because of single base mutation. However, a molecular understanding of the effect of these mutations is hampered by the lack of understanding of its catalytic mechanism. Here, we reconstruct the 3D EM structure of the PRS1 apo state. Together with the native stain EM structures of AMPNPP, AMPNPP and R5P, ADP and the apo states with distinct conformations, we suggest the hexamer is the enzymatically active form. Based on crystal structures, sequence analysis, mutagenesis, enzyme kinetics assays, and MD simulations, we reveal the conserved substrates binding motifs and make further analysis of all pathogenic mutants.

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Citations

Dec 30, 2016·Microbiology and Molecular Biology Reviews : MMBR·Bjarne Hove-JensenMartin Willemoës
May 12, 2020·Journal of Cellular and Molecular Medicine·Ting LiYijin Gao
Jun 6, 2017·Acta Crystallographica. Section F, Structural Biology Communications·Vladimir I TimofeevRoman S Esipov
Jul 12, 2020·International Journal of Molecular Sciences·Keemo Delos SantosNam-Sung Moon

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Methods Mentioned

BETA
X-ray

Software Mentioned

CCP4
Origin
GROMACS
HKL2000
Sparx
Spider
MOLREP
CCP4 package
MODELLER
Weblogo

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