PDBsum entry: 1n9a

Transferase

PDB id: 1n9a

Contents

Protein chains

312 a.a. *

401 a.a. *

Ligands

HFP

FTI

Metals

_ZN

* Residue conservation analysis

PDB id:

1n9a

Name:

Transferase

Title:

Farnesyltransferase complex with tetrahydropyridine inhibitors

Structure:

Protein farnesyltransferase alpha subunit. Chain: a. Fragment: residue 55-369. Synonym: caax farnesyltransferase alpha subunit, ras proteins prenyltransferase alpha, ftase-alpha. Engineered: yes. Protein farnesyltransferase beta subunit. Chain: b. Fragment: residue 22-423.

Source:

Rattus norvegicus. Norway rat. Organism_taxid: 10116. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108.

Biol. unit:

Dimer (from PQS)

Resolution:

3.20Å R-factor: 0.329 R-free: 0.375

Authors:

S.L.Gwaltney Ii,S.J.O'Conner,L.T.Nelson,G.M.Sullivan, H.Imade,W.Wang,L.Hasvold,Q.Li,J.Cohen,W.Z.Gu

Key ref:

S.L.Gwaltney et al. (2003). Aryl tetrahydropyridine inhibitors of farnesyltransferase: bioavailable analogues with improved cellular potency. Bioorg Med Chem Lett, 13, 1363-1366. PubMed id: 12657283 DOI: 10.1016/S0960-894X(03)00094-5

Date:

22-Nov-02 Release date: 07-Jan-03

Protein chain

Q04631  (FNTA_RAT) -  Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha

Seq: 377 a.a.

Struc: 312 a.a.*

Protein chain

Q02293  (FNTB_RAT) -  Protein farnesyltransferase subunit beta

Seq: 437 a.a.

Struc: 401 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.5.1.58 - Protein farnesyltransferase.
• Reaction: Farnesyl diphosphate + protein-cysteine = S-farnesyl protein + diphosphate

Farnesyl diphosphate (Bound ligand (Het Group name = HFP) matches with 57.00% similarity) + protein-cysteine = S-farnesyl protein + diphosphate

• Cofactor: Magnesium; Zinc
• Enzyme class 2: Chain A: E.C.2.5.1.59 - Protein geranylgeranyltransferase type I.
• Reaction: Geranylgeranyl diphosphate + protein-cysteine = S-geranylgeranyl- protein + diphosphate

Geranylgeranyl diphosphate (Bound ligand (Het Group name = HFP) matches with 48.00% similarity) + protein-cysteine = S-geranylgeranyl- protein + diphosphate

• Cofactor: Zinc

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

 Gene Ontology (GO) functional annotation 

• Cellular component: protein complex (2 terms)
• Biological process: response to inorganic substance (11 terms)
• Biochemical function: catalytic activity (12 terms)

reference

DOI no: 10.1016/S0960-894X(03)00094-5

Bioorg Med Chem Lett 13:1363-1366 (2003)

PubMed id: 12657283

Aryl tetrahydropyridine inhibitors of farnesyltransferase: bioavailable analogues with improved cellular potency.

S.L.Gwaltney, S.J.O'Connor, L.T.Nelson, G.M.Sullivan, H.Imade, W.Wang, L.Hasvold, Q.Li, J.Cohen, W.Z.Gu, S.K.Tahir, J.Bauch, K.Marsh, S.C.Ng, D.J.Frost, H.Zhang, S.Muchmore, C.G.Jakob, V.Stoll, C.Hutchins, S.H.Rosenberg, H.L.Sham.

ABSTRACT

Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered bioavailable aryl tetrahydropyridines that are potent in cell culture. The design, synthesis, SAR and biological properties of these compounds will be discussed.