5CG5

Neutron crystal structure of human farnesyl pyrophosphate synthase in complex with risedronate

Summary for 5CG5

• Entry DOI: 10.2210/pdb5cg5/pdb
• Related: 5cg6
• Descriptor: Farnesyl pyrophosphate synthase, MAGNESIUM ION, 1-HYDROXY-2-(3-PYRIDINYL)ETHYLIDENE BIS-PHOSPHONIC ACID, ... (4 entities in total)
• Functional Keywords: prenyl transferase, bisphophonate, osteoprosis, inhibitor, transferase-transferase inhibotor complex, transferase/transferase inhibotor
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 41386.88

Authors

Yokoyama, T.,Mizuguchi, M.,Ostermann, A.,Kusaka, K.,Niimura, N.,Schrader, T.E.,Tanaka, I. (deposition date: 2015-07-09, release date: 2015-10-14, Last modification date: 2024-04-03)

Primary citation

Yokoyama, T.,Mizuguchi, M.,Ostermann, A.,Kusaka, K.,Niimura, N.,Schrader, T.E.,Tanaka, I.
Protonation State and Hydration of Bisphosphonate Bound to Farnesyl Pyrophosphate Synthase
J.Med.Chem., 58:7549-7556, 2015

PubMed Abstract: Farnesyl pyrophosphate synthase (FPPS) catalyzes the condensation of isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate to FPP and is known to be a molecular target of osteoporosis drugs, such as risedronate (RIS), which is a nitrogen-containing bisphosphonate. The protonation states and hydration structure of RIS bound to FPPS were determined by neutron protein crystallography, which allows direct visualization of hydrogens and deuteriums. The structure analysis revealed that the phosphate groups of RIS were fully deprotonated with the abnormally decreased pKa, and that the roles of E93 and D264 consisted of canceling the extra negative charges upon the binding of ligands. Collectively, our neutron structures provided insights into the physicochemical properties during the bisphosphonate binding event.

PubMed: 26314394
DOI: 10.1021/acs.jmedchem.5b01147

Experimental method

NEUTRON DIFFRACTION (2.4 Å)
X-RAY DIFFRACTION (1.402 Å)