PDBsum entry 4lph

Transferase/transferase inhibitor

PDB id: 4lph

Contents

Protein chain

342 a.a.

Ligands

PO4

YL3

Waters ×50

PDB id:

4lph

Name:

Transferase/transferase inhibitor

Title:

Crystal structure of human fpps in complex with cl03093

Structure:

Farnesyl pyrophosphate synthase. Chain: f. Fragment: unp residues 67-419. Synonym: fpp synthase, 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. Expression_system_taxid: 562

Resolution:

2.30Å R-factor: 0.186 R-free: 0.226

Authors:

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

Key ref:

J.W.De Schutter et al. (2014). Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases. J Med Chem, 57, 5764-5776. PubMed id: 24911527 DOI: 10.1021/jm500629e

Date:

16-Jul-13 Release date: 25-Jun-14

Protein chain

P14324  (FPPS_HUMAN) -  Farnesyl pyrophosphate synthase from Homo sapiens

Seq: 419 a.a.

Struc: 342 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 = PO4) matches with 55.56% similarity)

• 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 = PO4) matches with 55.56% similarity)

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/jm500629e

J Med Chem 57:5764-5776 (2014)

PubMed id: 24911527

Multistage screening reveals chameleon ligands of the human farnesyl pyrophosphate synthase: implications to drug discovery for neurodegenerative diseases.

J.W.De Schutter, J.Park, C.Y.Leung, P.Gormley, Y.S.Lin, Z.Hu, A.M.Berghuis, J.Poirier, Y.S.Tsantrizos.

ABSTRACT

Human farnesyl pyrophosphate synthase (hFPPS) is the gate-keeper of mammalian isoprenoids and the key target of bisphosphonate drugs. Bisphosphonates suffer from poor "drug-like" properties and are mainly effective in treating skeletal diseases. Recent investigations have implicated hFPPS in various nonskeletal diseases, including Alzheimer's disease (AD). Analysis of single nucleotide polymorphisms in the hFPPS gene and mRNA levels in autopsy-confirmed AD subjects was undertaken, and a genetic link between hFPPS and phosphorylated tau (P-Tau) levels in the human brain was identified. Elevated P-Tau levels are strongly implicated in AD progression. The development of nonbisphosphonate inhibitors can provide molecular tools for validating hFPPS as a therapeutic target for tauopathy-associated neurodegeneration. A multistage screening protocol led to the identification of a new monophosphonate chemotype that bind in an allosteric pocket of hFPPS. Optimization of these compounds could lead to human therapeutics that block tau metabolism and arrest the progression of neurodegeneration.