5OFW

Crystal structure of human 3-phosphoglycerate dehydrogenase in complex with 3-Chloro-4-fluorobenzamide

5OFW の概要

• エントリーDOI: 10.2210/pdb5ofw/pdb
• 分子名称: D-3-phosphoglycerate dehydrogenase, 3-chloranyl-4-fluoranyl-benzamide (3 entities in total)
• 機能のキーワード: dehydrogenase, serine metabolism, fbdd, 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: 48214.50

構造登録者

Unterlass, J.E.,Basle, A.,Blackburn, T.J.,Tucker, J.,Cano, C.,Noble, M.E.M.,Curtin, N.J. (登録日: 2017-07-11, 公開日: 2017-08-16, 最終更新日: 2024-05-08)

主引用文献

Unterlass, J.E.,Basle, A.,Blackburn, T.J.,Tucker, J.,Cano, C.,Noble, M.E.M.,Curtin, N.J.
Validating and enabling phosphoglycerate dehydrogenase (PHGDH) as a target for fragment-based drug discovery in PHGDH-amplified breast cancer.
Oncotarget, 9:13139-13153, 2018

PubMed Abstract: 3-Phosphoglycerate dehydrogenase (PHGDH) has recently been identified as an attractive target in cancer therapy as it links upregulated glycolytic flux to increased biomass production in cancer cells. PHGDH catalyses the first step in the serine synthesis pathway and thus diverts glycolytic flux into serine synthesis. We have used siRNA-mediated suppression of PHGDH expression to show that PHGDH is a potential therapeutic target in -amplified breast cancer. Knockdown caused reduced proliferation in the -amplified cell line MDA-MB-468, whereas breast cancer cells with low PHGDH expression or with elevated PHGDH expression in the absence of genomic amplification were not affected. As a first step towards design of a chemical probe for PHGDH, we report a fragment-based drug discovery approach for the identification of PHGDH inhibitors. We designed a truncated PHGDH construct that gave crystals which diffracted to high resolution, and could be used for fragment soaking. 15 fragments stabilising PHGDH were identified using a thermal shift assay and validated by X-ray crystallography and ITC competition experiments to exhibit 1.5-26.2 mM affinity for PHGDH. A structure-guided fragment growing approach was applied to the PHGDH binders from the initial screen, yielding greater understanding of the binding site and suggesting routes to achieve higher affinity NAD-competitive inhibitors.

PubMed: 29568346
DOI: 10.18632/oncotarget.11487

実験手法

X-RAY DIFFRACTION (1.5 Å)