US 7,467,046 B2Granted

Geranylgeranyl transferase type I (GGTase-I) structure and uses thereof

AssigneeDuke University

InventorsJeffrey S. Taylor, T. Scott Reid, Lorena S. Beese

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Abstract

Protein geranylgeranyl transferase type I (GGTase-I), a Ca1a2X prenyltransferase, is an essential enzyme in eukaryotes. GGTase-I catalyzes the carboxyl-terminal lipidation of over one hundred proteins, including many GTP-binding regulatory proteins (G proteins). The presently disclosed subject matter comprises a plurality of crystal structures of mammalian GGTase-I in complex with substrates and products that provide the first structural information for this enzyme, facilitating the elucidation of a generalized method of action for all protein prenyltransferases; the method includes a role in product transport. The structures reveal specificity determinants that allow classification of putative protein prenyltransferase sequences and can facilitate optimization of GGTase-I and FTase modulators.

Claims7

Dependent claims

A method for designing a ligand for a farnesyl transferase (ETase), the method comprising:

(a) providing a molecule that binds to a geranylgeranyl transferase type I (GGTase-l) a2 site;
(b) determining a moiety of the molecule that interacts with the GGTase-I a2 site;
(c) modifying the moiety to produce a modified molecule;
wherein the modifying comprises modifying a moiety that interacts with one or more of residues Thr491β, Phe 106β, and Leu 361β of a human GGTase-I polypeptide;
(d) modeling a first interaction between the modified molecule and the GGTase-I a2 sites
(e) modeling a second interaction between the modified molecule with an FTase a2site;
(f) identifying in a modified molecule that is predicted to be unable to bind to the GGTase-I a2 site but able to bind to the FTase a2 site;
and
(g) displaying a structure of the modified molecule identified in step (f),
whereby a ligand for a FTase is designed.

7 more elements

Dependencies are inferred from the claim text.

Facts

Application: 10/957,517Filed 1 Oct 2004 · us provisional application
Priority: 1 Oct 2003
Published: US 2005/0221459 A16 Oct 2005
Granted: 16 Dec 2008
Term ends: Not estimatedThe source records don’t support an estimate.

Classification16 codes

C12N 9/1085
Transferases: transferring alkyl or aryl groups other than methyl groups
C12Q 1/48
Measuring or testing processes involving enzymes, nucleic acids or microorganisms ; Compositions therefor; Processes of preparing such…
C12Y 205/01029
Transferring alkyl or aryl groups, other than methyl groups: geranylgeranyl diphosphate synthase
G16B 15/30
ICT specially adapted for analysing two-dimensional [2D] or three-dimensional [3D] molecular structures, e.g. structural or functional relations…:…

Family

Application60/507,685Us provisional application · filed 1 Oct 2003
US 2005/0221459 A1Pre-grant publication · published 6 Oct 2005
US 7,467,046 B2This patent

From the US filing history. Foreign family members aren’t listed.

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