1LD7: Co-Crystal Structure Of Human Farnesyltransferase With Farnesyldiphosphate And Inhibitor Compound 66

Citation:
Abstract
A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.
PDB ID: 1LD7Download
MMDB ID: 19949
PDB Deposition Date: 2002/4/8
Updated in MMDB: 2007/10
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Similar Structures:
Biological Unit for 1LD7: dimeric; determined by author and by software (PISA)
Molecular Components in 1LD7
Label Count Molecule
Proteins (2 molecules)
1
Protein Farnesyltransferase Alpha Subunit(Gene symbol: FNTA)
Molecule annotation
1
Protein Farnesyltransferase Beta Subunit(Gene symbol: FNTB)
Molecule annotation
Chemicals (4 molecules)
1
1
2
1
3
1
4
1
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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