PDBsum entry 5dgs

Transferase

PDB id: 5dgs

Contents

Protein chain

343 a.a.

Ligands

5A7

Waters ×48

PDB id:

5dgs

Name:

Transferase

Title:

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

Structure:

Farnesyl pyrophosphate synthase. Chain: f. Fragment: unp residues 72-419. Synonym: fps,(2e,6e)-farnesyl diphosphate synthase, dimethylallyltranstransferase,farnesyl diphosphate synthase, geranyltranstransferase. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fdps, fps, kiaa1293. Expressed in: escherichia coli bl21(de3). Expression_system_taxid: 469008. Expression_system_variant: tuner.

Resolution:

2.62Å R-factor: 0.193 R-free: 0.243

Authors:

J.M.Rondeau,E.Bourgier,S.Lehmann

Key ref:

W.Jahnke et al. (2015). A General Strategy for Targeting Drugs to Bone. Angew Chem Int Ed Engl, 54, 14575-14579. PubMed id: 26457482 DOI: 10.1002/anie.201507064

Date:

28-Aug-15 Release date: 13-Jul-16

Protein chain

P14324  (FPPS_HUMAN) -  Farnesyl pyrophosphate synthase from Homo sapiens

Seq: 419 a.a.

Struc: 343 a.a.

Enzyme reactions

• Enzyme class 1: E.C.2.5.1.1 - dimethylallyltranstransferase.
• Pathway: Terpenoid biosynthesis
• Reaction: isopentenyl diphosphate + dimethylallyl diphosphate = (2E)- geranyl diphosphate + diphosphate
• Enzyme class 2: E.C.2.5.1.10 - (2E,6E)-farnesyl diphosphate synthase.

Pathway:

• Reaction: isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

reference

DOI no: 10.1002/anie.201507064

Angew Chem Int Ed Engl 54:14575-14579 (2015)

PubMed id: 26457482

A General Strategy for Targeting Drugs to Bone.

W.Jahnke, G.Bold, A.L.Marzinzik, S.Ofner, X.Pellé, S.Cotesta, E.Bourgier, S.Lehmann, C.Henry, R.Hemmig, F.Stauffer, J.C.Hartwieg, J.R.Green, J.M.Rondeau.

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.