5N6C

Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with NAD and L-Tartrate

5N6C の概要

• エントリーDOI: 10.2210/pdb5n6c/pdb
• 分子名称: D-3-phosphoglycerate dehydrogenase, L(+)-TARTARIC ACID, NICOTINAMIDE-ADENINE-DINUCLEOTIDE, ... (4 entities in total)
• 機能のキーワード: dehydrogenase, serine metabolism, enzymology, oxidoreductase
• 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: 65788.90

構造登録者

Unterlass, J.E.,Basle, A.,Tucker, J.,Cano, C.,Noble, M.E.M.,Curtin, N.J. (登録日: 2017-02-14, 公開日: 2017-11-22, 最終更新日: 2024-01-17)

主引用文献

Unterlass, J.E.,Wood, R.J.,Basle, A.,Tucker, J.,Cano, C.,Noble, M.M.E.,Curtin, N.J.
Structural insights into the enzymatic activity and potential substrate promiscuity of human 3-phosphoglycerate dehydrogenase (PHGDH).
Oncotarget, 8:104478-104491, 2017

PubMed Abstract: Cancer cells reprogram their metabolism and energy production to sustain increased growth, enable metastasis and overcome resistance to cancer treatments. Although primary roles for many metabolic proteins have been identified, some are promiscuous in regards to the reaction they catalyze. To efficiently target these enzymes, a good understanding of their enzymatic function and structure, as well as knowledge regarding any substrate or catalytic promiscuity is required. Here we focus on the characterization of human 3-phosphoglycerate dehydrogenase (PHGDH). PHGDH catalyzes the NAD-dependent conversion of 3-phosphoglycerate to phosphohydroxypyruvate, which is the first step in the synthesis pathway of serine, a critical amino acid for protein and nucleic acid biosynthesis. We have investigated substrate analogues to assess whether PHGDH might possess other enzymatic roles that could explain its occasional over-expression in cancer, as well as to help with the design of specific inhibitors. We also report the crystal structure of the catalytic subunit of human PHGDH, a dimer, solved with bound cofactor in one monomer and both cofactor and -tartrate in the second monomer. enzyme activity measurements show that the catalytic subunit of PHGDH is still active and that PHGDH activity could be significantly inhibited with adenosine 5'-diphosphoribose.

PubMed: 29262655
DOI: 10.18632/oncotarget.22327

実験手法

X-RAY DIFFRACTION (2.3 Å)