Structure of Protein Geranylgeranyltransferase-I from the Human Pathogen Candida albicans Complexed with a Lipid Substrate

Journal Article · Fri Nov 21 04:00:00 EST 2008 · J. Biol. Chem.

DOI:https://doi.org/10.1074/jbc.M805330200· OSTI ID:1006954

Hast, Michael A; Beese, Lorena S ^[1]

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1. Duke

Protein geranylgeranyltransferase-I (GGTase-I) catalyzes the transfer of a 20-carbon isoprenoid lipid to the sulfur of a cysteine residue located near the C terminus of numerous cellular proteins, including members of the Rho superfamily of small GTPases and other essential signal transduction proteins. In humans, GGTase-I and the homologous protein farnesyltransferase (FTase) are targets of anticancer therapeutics because of the role small GTPases play in oncogenesis. Protein prenyltransferases are also essential for many fungal and protozoan pathogens that infect humans, and have therefore become important targets for treating infectious diseases. Candida albicans, a causative agent of systemic fungal infections in immunocompromised individuals, is one pathogen for which protein prenylation is essential for survival. Here we present the crystal structure of GGTase-I from C. albicans (CaGGTase-I) in complex with its cognate lipid substrate, geranylgeranylpyrophosphate. This structure provides a high-resolution picture of a non-mammalian protein prenyltransferase. There are significant variations between species in critical areas of the active site, including the isoprenoid-binding pocket, as well as the putative product exit groove. These differences indicate the regions where specific protein prenyltransferase inhibitors with antifungal activity can be designed.

• Research Organization: Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
• Sponsoring Organization: USDOE
• OSTI ID: 1006954
• Journal Information: J. Biol. Chem., Journal Name: J. Biol. Chem. Journal Issue: (46) ; 11, 2008 Vol. 283; ISSN JBCHA3; ISSN 0021-9258
• Country of Publication: United States
• Language: ENGLISH

Related Subjects

36 MATERIALS SCIENCE
CANDIDA
CRYSTAL STRUCTURE
CYSTEINE
HUMAN POPULATIONS
INFECTIOUS DISEASES
LIPIDS
PATHOGENS
PROTEINS
RESIDUES
SIGNALS
SUBSTRATES
SULFUR
VARIATIONS