4JVJ: Crystal Structure Of Human Fpps In Complex With Magnesium, Cl01131, And Sulfate

Citation:
Abstract
Human farnesyl pyrophosphate synthase (hFPPS) controls the post-translational prenylation of small GTPase proteins that are essential for cell signaling, cell proliferation, and osteoclast-mediated bone resorption. Inhibition of hFPPS is a clinically validated mechanism for the treatment of lytic bone diseases, including osteoporosis and cancer related bone metastases. A new series of thienopyrimidine-based bisphosphonates (ThP-BPs) were identified that inhibit hFPPS with low nanomolar potency. Crystallographic evidence revealed binding of ThP-BP inhibitors in the allylic subpocket of hFPPS. Simultaneous binding of inorganic pyrophosphate in the IPP subpocket leads to conformational closing of the active site cavity. The ThP-BP analogues are significantly less hydrophilic yet exhibit higher affinity for the bone mineral hydroxyapatite than the current N-BP drug risedronic acid. The antiproliferation properties of a potent ThB-BP analogue was assessed in a multiple myeloma cell line and found to be equipotent to the best current N-BP drugs. Consequently, these compounds represent a new structural class of hFPPS inhibitors and a novel scaffold for the development of human therapeutics.
PDB ID: 4JVJDownload
MMDB ID: 116374
PDB Deposition Date: 2013/3/25
Updated in MMDB: 2014/01
Experimental Method:
x-ray diffraction
Resolution: 2.8  Å
Source Organism:
Similar Structures:
Biological Unit for 4JVJ: dimeric; determined by author and by software (PISA)
Molecular Components in 4JVJ
Label Count Molecule
Proteins (2 molecules)
2
Farnesyl Pyrophosphate Synthase(Gene symbol: FDPS)
Molecule annotation
Chemicals (10 molecules)
1
2
2
2
3
6
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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