8WR2

Crystal Structure of Human Pyridoxal Kinase with bound Luteolin

Summary for 8WR2

• Entry DOI: 10.2210/pdb8wr2/pdb
• Related PRD ID: PRD_900006
• Descriptor: Pyridoxal kinase, alpha-D-glucopyranose-(1-1)-alpha-D-glucopyranose, SODIUM ION, ... (7 entities in total)
• Functional Keywords: inhibitor, luteolin, pdxk, complex, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 72611.15

Authors

Fan, J.,Zhu, Y. (deposition date: 2023-10-12, release date: 2024-03-20)

Primary citation

Zhu, Y.,Bao, G.,Zhu, G.,Zhang, K.,Zhu, S.,Hu, J.,He, J.,Jiang, W.,Fan, J.,Dang, Y.
Discovery and characterization of natural product luteolin as an effective inhibitor of human pyridoxal kinase.
Bioorg.Chem., 143:107057-107057, 2024

PubMed Abstract: Pyridoxal kinase (PDXK) is an essential enzyme in the synthesis of pyridoxal 5-phosphate (PLP), the active form of vitamin B6, which plays a pivotal role in maintaining the enzyme activity necessary for cell metabolism. Thus, PDXK has garnered attention as a potential target for metabolism regulation and tumor therapy. Despite this interest, existing PDXK inhibitors have faced limitations, including weak suppressive activity, unclear mechanisms of action, and associated toxic side effects. In this study, we present the discovery of a novel PDXK inhibitor, luteolin, through a high-throughput screening approach based on enzyme activity. Luteolin, a natural product, exhibits micromolar-level affinity for PDXK and effectively inhibits the enzyme's activity in vitro. Our crystal structures reveal that luteolin occupies the ATP binding pocket through hydrophobic interactions and a weak hydrogen bonding pattern, displaying reversible characteristics as confirmed by biochemical assays. Moreover, luteolin disrupts vitamin B6 metabolism by targeting PDXK, thereby inhibiting the proliferation of leukemia cells. This research introduces a novel screening method for identifying high-affinity and potent PDXK inhibitors and sheds light on clarification of the structural mechanism of PDXK-luteolin for subsequent structure optimization of inhibitors.

PubMed: 38150934
DOI: 10.1016/j.bioorg.2023.107057

Experimental method

X-RAY DIFFRACTION (1.94 Å)