4OX2

I45T cytosolic phosphoenolpyruvate carboxykinase in complex with beta-sulfopyruvate and GTP

Summary for 4OX2

• Entry DOI: 10.2210/pdb4ox2/pdb
• Descriptor: Phosphoenolpyruvate carboxykinase, cytosolic [GTP], MANGANESE (II) ION, GUANOSINE-5'-TRIPHOSPHATE, ... (8 entities in total)
• Functional Keywords: kinase, gluconeogenesis, lyase
• Biological source: Rattus norvegicus (Rat)
• Total number of polymer chains: 2
• Total formula weight: 141300.11

Authors

Holyoak, T. (deposition date: 2014-02-04, release date: 2014-06-11, Last modification date: 2023-09-27)

Primary citation

Adams, D.R.,Yuan, H.,Holyoak, T.,Arajs, K.H.,Hakimi, P.,Markello, T.C.,Wolfe, L.A.,Vilboux, T.,Burton, B.K.,Fajardo, K.F.,Grahame, G.,Holloman, C.,Sincan, M.,Smith, A.C.,Wells, G.A.,Huang, Y.,Vega, H.,Snyder, J.P.,Golas, G.A.,Tifft, C.J.,Boerkoel, C.F.,Hanson, R.W.,Traynelis, S.F.,Kerr, D.S.,Gahl, W.A.
Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity.
Mol.Genet.Metab., 113:161-170, 2014

PubMed Abstract: The National Institutes of Health Undiagnosed Diseases Program evaluates patients for whom no diagnosis has been discovered despite a comprehensive diagnostic workup. Failure to diagnose a condition may arise from the mutation of genes previously unassociated with disease. However, we hypothesized that this could also co-occur with multiple genetic disorders. Demonstrating a complex syndrome caused by multiple disorders, we report two siblings manifesting both similar and disparate signs and symptoms. They shared a history of episodes of hypoglycemia and lactic acidosis, but had differing exam findings and developmental courses. Clinical acumen and exome sequencing combined with biochemical and functional studies identified three genetic conditions. One sibling had Smith-Magenis Syndrome and a nonsense mutation in the RAI1 gene. The second sibling had a de novo mutation in GRIN2B, which resulted in markedly reduced glutamate potency of the encoded receptor. Both siblings had a protein-destabilizing homozygous mutation in PCK1, which encodes the cytosolic isoform of phosphoenolpyruvate carboxykinase (PEPCK-C). In summary, we present the first clinically-characterized mutation of PCK1 and demonstrate that complex medical disorders can represent the co-occurrence of multiple diseases.

PubMed: 24863970
DOI: 10.1016/j.ymgme.2014.04.001

Experimental method

X-RAY DIFFRACTION (2 Å)