3E34

Protein farnesyltransferase complexed with FPP and ethylenediamine-scaffold inhibitor 10

Summary for 3E34

• Entry DOI: 10.2210/pdb3e34/pdb
• Related: 1D8D 1KZO 1KZP 1SA4 1SA5 2IEJ 3E30 3E32 3E33 3E37
• Descriptor: Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha, Protein farnesyltransferase subunit beta, ZINC ION, ... (6 entities in total)
• Functional Keywords: ftase, protein farnesyltransferase, farnesyltransferase, malaria, plasmodium, falciparum, antimalarial, ethylenediamine, prenyltransferase, transferase, metal-binding, phosphoprotein, zinc
• Biological source: Rattus norvegicus (rat); More
• Total number of polymer chains: 2
• Total formula weight: 94009.07

Authors

Hast, M.A.,Beese, L.S. (deposition date: 2008-08-06, release date: 2009-03-10, Last modification date: 2024-02-21)

Primary citation

Hast, M.A.,Fletcher, S.,Cummings, C.G.,Pusateri, E.E.,Blaskovich, M.A.,Rivas, K.,Gelb, M.H.,Van Voorhis, W.C.,Sebti, S.M.,Hamilton, A.D.,Beese, L.S.
Structural basis for binding and selectivity of antimalarial and anticancer ethylenediamine inhibitors to protein farnesyltransferase.
Chem.Biol., 16:181-192, 2009

PubMed Abstract: Protein farnesyltransferase (FTase) catalyzes an essential posttranslational lipid modification of more than 60 proteins involved in intracellular signal transduction networks. FTase inhibitors have emerged as a significant target for development of anticancer therapeutics and, more recently, for the treatment of parasitic diseases caused by protozoan pathogens, including malaria (Plasmodium falciparum). We present the X-ray crystallographic structures of complexes of mammalian FTase with five inhibitors based on an ethylenediamine scaffold, two of which exhibit over 1000-fold selective inhibition of P. falciparum FTase. These structures reveal the dominant determinants in both the inhibitor and enzyme that control binding and selectivity. Comparison to a homology model constructed for the P. falciparum FTase suggests opportunities for further improving selectivity of a new generation of antimalarial inhibitors.

PubMed: 19246009
DOI: 10.1016/j.chembiol.2009.01.014

Experimental method

X-RAY DIFFRACTION (2.05 Å)