5DGS

Crystal structure of human FPPS in complex with the monophosphonate compound 15

Summary for 5DGS

• Entry DOI: 10.2210/pdb5dgs/pdb
• Related: 5DGM 5DGN
• Descriptor: Farnesyl pyrophosphate synthase, {(E)-2-[6-(acetylamino)-8-(naphthalen-1-yl)quinolin-2-yl]ethenyl}phosphonic acid (3 entities in total)
• Functional Keywords: transferase, isoprene biosynthesis, cholesterol biosynthesis
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P14324
• Total number of polymer chains: 1
• Total formula weight: 40602.24

Authors

Rondeau, J.M.,Bourgier, E.,Lehmann, S. (deposition date: 2015-08-28, release date: 2016-07-13, Last modification date: 2024-05-08)

Primary citation

Jahnke, W.,Bold, G.,Marzinzik, A.L.,Ofner, S.,Pelle, X.,Cotesta, S.,Bourgier, E.,Lehmann, S.,Henry, C.,Hemmig, R.,Stauffer, F.,Hartwieg, J.C.,Green, J.R.,Rondeau, J.M.
A General Strategy for Targeting Drugs to Bone.
Angew.Chem.Int.Ed.Engl., 54:14575-14579, 2015

PubMed Abstract: Targeting drugs to their desired site of action can increase their safety and efficacy. Bisphosphonates are prototypical examples of drugs targeted to bone. However, bisphosphonate bone affinity is often considered too strong and cannot be significantly modulated without losing activity on the enzymatic target, farnesyl pyrophosphate synthase (FPPS). Furthermore, bisphosphonate bone affinity comes at the expense of very low and variable oral bioavailability. FPPS inhibitors were developed with a monophosphonate as a bone-affinity tag that confers moderate affinity to bone, which can furthermore be tuned to the desired level, and the relationship between structure and bone affinity was evaluated by using an NMR-based bone-binding assay. The concept of targeting drugs to bone with moderate affinity, while retaining oral bioavailability, has broad application to a variety of other bone-targeted drugs.

PubMed: 26457482
DOI: 10.1002/anie.201507064

Experimental method

X-RAY DIFFRACTION (2.62 Å)