4K10

Crystal Structure of Leshmaniasis major Farnesyl diphosphate synthase in complex with 3-FLUORO-1-(2-HYDROXY-2,2-DIPHOSPHONOETHYL)PYRIDINIUM and Mg2+

Summary for 4K10

• Entry DOI: 10.2210/pdb4k10/pdb
• Related: 4JZB 4JZX
• Descriptor: Farnesyl pyrophosphate synthase, SODIUM ION, MAGNESIUM ION, ... (8 entities in total)
• Functional Keywords: geranyl transferase, fpps, farnesyl pyrophosphate synthase, farnesyl diphosphate synthase, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• Biological source: Leishmania major
• Total number of polymer chains: 4
• Total formula weight: 166029.05

Authors

Aripirala, S.,Gabelli, S.,Amzel, L.M. (deposition date: 2013-04-04, release date: 2014-04-02, Last modification date: 2024-02-28)

Primary citation

Aripirala, S.,Gonzalez-Pacanowska, D.,Oldfield, E.,Kaiser, M.,Amzel, L.M.,Gabelli, S.B.
Structural and thermodynamic basis of the inhibition of Leishmania major farnesyl diphosphate synthase by nitrogen-containing bisphosphonates.
Acta Crystallogr.,Sect.D, 70:802-810, 2014

PubMed Abstract: Farnesyl diphosphate synthase (FPPS) is an essential enzyme involved in the biosynthesis of sterols (cholesterol in humans and ergosterol in yeasts, fungi and trypanosomatid parasites) as well as in protein prenylation. It is inhibited by bisphosphonates, a class of drugs used in humans to treat diverse bone-related diseases. The development of bisphosphonates as antiparasitic compounds targeting ergosterol biosynthesis has become an important route for therapeutic intervention. Here, the X-ray crystallographic structures of complexes of FPPS from Leishmania major (the causative agent of cutaneous leishmaniasis) with three bisphosphonates determined at resolutions of 1.8, 1.9 and 2.3 Å are reported. Two of the inhibitors, 1-(2-hydroxy-2,2-diphosphonoethyl)-3-phenylpyridinium (300B) and 3-butyl-1-(2,2-diphosphonoethyl)pyridinium (476A), co-crystallize with the homoallylic substrate isopentenyl diphosphate (IPP) and three Ca(2+) ions. A third inhibitor, 3-fluoro-1-(2-hydroxy-2,2-diphosphonoethyl)pyridinium (46I), was found to bind two Mg(2+) ions but not IPP. Calorimetric studies showed that binding of the inhibitors is entropically driven. Comparison of the structures of L. major FPPS (LmFPPS) and human FPPS provides new information for the design of bisphosphonates that will be more specific for inhibition of LmFPPS. The asymmetric structure of the LmFPPS-46I homodimer indicates that binding of the allylic substrate to both monomers of the dimer results in an asymmetric dimer with one open and one closed homoallylic site. It is proposed that IPP first binds to the open site, which then closes, opening the site on the other monomer, which closes after binding the second IPP, leading to the symmetric fully occupied FPPS dimer observed in other structures.

PubMed: 24598749
DOI: 10.1107/S1399004713033221

Experimental method

X-RAY DIFFRACTION (2.3 Å)