6UIQ

Crystal structure of wild-type human phosphoglucomutase 1 in complex with Glucose-6-Phosphate

Replaces:  6BJ0

Summary for 6UIQ

• Entry DOI: 10.2210/pdb6uiq/pdb
• Related: 5EPC
• Descriptor: phosphoglucomutase-1, 6-O-phosphono-alpha-D-glucopyranose, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: phosphoglucomutase, g6p, isomerase
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 128952.35

Authors

Stiers, K.M.,Beamer, L.J. (deposition date: 2019-10-01, release date: 2020-08-12, Last modification date: 2023-10-11)

Primary citation

Stiers, K.M.,Beamer, L.J.
A Hotspot for Disease-Associated Variants of Human PGM1 Is Associated with Impaired Ligand Binding and Loop Dynamics.
Structure, 26:1337-1345.e3, 2018

PubMed Abstract: Human phosphoglucomutase 1 (PGM1) plays a central role in cellular glucose homeostasis, catalyzing the conversion of glucose 1-phosphate and glucose 6-phosphate. Recently, missense variants of this enzyme were identified as causing an inborn error of metabolism, PGM1 deficiency, with features of a glycogen storage disease and a congenital disorder of glycosylation. Previous studies of selected PGM1 variants have revealed various mechanisms for enzyme dysfunction, including regions of structural disorder and side-chain rearrangements within the active site. Here, we examine variants within a substrate-binding loop in domain 4 (D4) of PGM1 that cause extreme impairment of activity. Biochemical, structural, and computational studies demonstrate multiple detrimental impacts resulting from these variants, including loss of conserved ligand-binding interactions and reduced mobility of the D4 loop, due to perturbation of its conformational ensemble. These potentially synergistic effects make this conserved ligand-binding loop a hotspot for disease-related variants in PGM1 and related enzymes.

PubMed: 30122451
DOI: 10.1016/j.str.2018.07.005

Experimental method

X-RAY DIFFRACTION (2.3 Å)