4LPG

Crystal structure of human FPPS in complex with CL01131

Summary for 4LPG

• Entry DOI: 10.2210/pdb4lpg/pdb
• Related: 4JPH
• Descriptor: Farnesyl pyrophosphate synthase, PHOSPHATE ION, ({[6-(4-methylphenyl)thieno[2,3-d]pyrimidin-4-yl]amino}methanediyl)bis(phosphonic acid), ... (4 entities in total)
• Functional Keywords: transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 43655.25

Authors

Park, J.,Leung, C.Y.,Tsantrizos, Y.S.,Berghuis, A.M. (deposition date: 2013-07-16, release date: 2014-06-25, Last modification date: 2023-09-20)

Primary citation

De Schutter, J.W.,Park, J.,Leung, C.Y.,Gormley, P.,Lin, Y.S.,Hu, Z.,Berghuis, A.M.,Poirier, J.,Tsantrizos, Y.S.
Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.
J.Med.Chem., 57:5764-5776, 2014

PubMed Abstract: Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.

PubMed: 24911527
DOI: 10.1021/jm500629e

Experimental method

X-RAY DIFFRACTION (2.35 Å)