4GA3

Crystal Structure of Human Farnesyl Diphosphate Synthase in Complex with BPH-1260

Summary for 4GA3

• Entry DOI: 10.2210/pdb4ga3/pdb
• Descriptor: Farnesyl pyrophosphate synthase, 1-butyl-3-(2-hydroxy-2,2-diphosphonoethyl)-1H-imidazol-3-ium, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: all alpha helices, cytosol, transferase
• Biological source: Homo sapiens (human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 40621.75

Authors

Liu, Y.-L.,Zhang, Y.,Oldfield, E. (deposition date: 2012-07-24, release date: 2013-05-08, Last modification date: 2023-09-13)

Primary citation

Zhang, Y.,Zhu, W.,Liu, Y.L.,Wang, H.,Wang, K.,Li, K.,No, J.H.,Ayong, L.,Gulati, A.,Pang, R.,Freitas-Junior, L.,Morita, C.T.,Old-Field, E.
Chemo-Immunotherapeutic Anti-Malarials Targeting Isoprenoid Biosynthesis.
ACS MED.CHEM.LETT., 4:423-427, 2013

PubMed Abstract: We synthesized 30 lipophilic bisphosphonates and tested them in malaria parasite killing (targeting parasite geranylgeranyl diphosphate synthase, GGPPS) as well in human γδ T cell activation (targeting human farnesyl diphosphate synthase, FPPS). Similar patterns of activity were seen in inhibiting human FPPS and GGPPS, with short to medium chain-length species having most activity. In cells, shorter chain-length species had low activity, due to poor membrane permeability, and longer chain length species were poor enzyme inhibitors. Optimal activity was thus seen with ~C side-chains, which have the best combination of enzyme inhibition and cell penetration. We also solved the crystal structure of one potent inhibitor, bound to FPPS. The results are of interest since they suggest the possibility of a combined chemo/immuno-therapeutic approach to anti-malarial development in which both direct parasite killing as well as γδ T cell activation can be achieved with a single compound.

PubMed: 23610597
DOI: 10.1021/ml4000436

Experimental method

X-RAY DIFFRACTION (2.39 Å)