PDBsum entry 4l2x

Transferase/transferase inhibitor

PDB id: 4l2x

Contents

Protein chain

346 a.a.

Ligands

YL2

POP

Metals

_MG ×3

Waters ×15

PDB id:

4l2x

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of human fpps in complex with magnesium, cl02134, and inorganic pyrophosphate

Structure:

Farnesyl pyrophosphate synthase. Chain: f. Fragment: unp residues 67-419. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: fdps, fps, kiaa1293. Expressed in: escherichia coli. Expression_system_taxid: 562

Resolution:

2.55Å R-factor: 0.204 R-free: 0.257

Authors:

J.Park,C.-Y.Leung,Y.S.Tsantrizos,A.M.Berghuis

Key ref:

C.Y.Leung et al. (2013). Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition. J Med Chem, 56, 7939-7950. PubMed id: 23998921 DOI: 10.1021/jm400946f

Date:

04-Jun-13 Release date: 01-Jan-14

Protein chain

P14324  (FPPS_HUMAN) -  Farnesyl pyrophosphate synthase from Homo sapiens

Seq: 419 a.a.

Struc: 346 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

isopentenyl diphosphate + dimethylallyl diphosphate = (2E)- geranyl diphosphate + diphosphate (Bound ligand (Het Group name = POP) corresponds exactly)

• 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

isopentenyl diphosphate + (2E)-geranyl diphosphate = (2E,6E)-farnesyl diphosphate + diphosphate (Bound ligand (Het Group name = POP) corresponds exactly)

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: 10.1021/jm400946f

J Med Chem 56:7939-7950 (2013)

PubMed id: 23998921

Thienopyrimidine bisphosphonate (ThPBP) inhibitors of the human farnesyl pyrophosphate synthase: optimization and characterization of the mode of inhibition.

C.Y.Leung, J.Park, J.W.De Schutter, M.Sebag, A.M.Berghuis, Y.S.Tsantrizos.

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.