PDBsum entry 1mzc

Transferase

PDB id

1mzc

Loading ...

Contents

			Protein chains

					313 a.a. *


					407 a.a. *

			Ligands

					GLC-FRU


					FPP


					BNE

			Metals

					_ZN

			Waters ×703

* Residue conservation analysis

PDB id:

1mzc

Links

Name:

Transferase

Title:

Co-crystal structure of human farnesyltransferase with farnesyldiphosphate and inhibitor compound 33a

Structure:

Protein farnesyltransferase alpha subunit. Chain: a. Synonym: caax farnesyltransferase alpha subunit, ras proteins prenyltransferase alpha, ftase-alpha. Engineered: yes. Protein farnesyltransferase beta subunit. Chain: b. Synonym: caax farnesyltransferase beta subunit, ras proteins prenyltransferase beta, ftase-beta.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562. Expression_system_taxid: 562

Biol. unit:

Dimer (from PQS)

Resolution:

2.00Å

R-factor:

0.177

R-free:

0.205

Authors:

S.J.Desolms,T.M.Ciccarone,S.C.Mactough,A.W.Shaw,C.A.Buser,M.Ellis- Hutchings,C.Fernandes,K.A.Hamilton,H.E.Huber,N.E.Kohl,R.B.Lobell, R.G.Robinson,N.N.Tsou,E.S.Walsh,S.L.Graham,L.S.Beese,J.S.Taylor

Key ref:

S.J.deSolms et al. (2003). Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents. J Med Chem, 46, 2973-2984. PubMed id: 12825937 DOI: 10.1021/jm020587n

Date:

07-Oct-02

Release date:

08-Jul-03

PROCHECK

	Headers

	References

Protein chain

P49354 (FNTA_HUMAN) - Protein farnesyltransferase/geranylgeranyltransferase type-1 subunit alpha from Homo sapiens

Seq: Struc:					379 a.a. 313 a.a.

Protein chain

P49356 (FNTB_HUMAN) - Protein farnesyltransferase subunit beta from Homo sapiens

Seq: Struc:					437 a.a. 407 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class 1:

Chains A, B: E.C.2.5.1.58 - protein farnesyltransferase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

L-cysteinyl-[protein] + (2E,6E)-farnesyl diphosphate = S-(2E,6E)- farnesyl-L-cysteinyl-[protein] + diphosphate

L-cysteinyl-[protein] Bound ligand (Het Group name = FPP) corresponds exactly	+	(2E,6E)-farnesyl diphosphate	=	S-(2E,6E)- farnesyl-L-cysteinyl-[protein]	+	diphosphate

Cofactor:

Mg(2+); Zn(2+)

Enzyme class 2:

Chain A: E.C.2.5.1.59 - protein geranylgeranyltransferase type I.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

geranylgeranyl diphosphate + L-cysteinyl-[protein] = S-geranylgeranyl-L- cysteinyl-[protein] + diphosphate

geranylgeranyl diphosphate
Bound ligand (Het Group name = FPP)
matches with 82.76% similarity

L-cysteinyl-[protein]

S-geranylgeranyl-L- cysteinyl-[protein]

diphosphate

Cofactor:

Zn(2+)

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

reference

DOI no: 10.1021/jm020587n	J Med Chem 46:2973-2984 (2003)
PubMed id: 12825937

Dual protein farnesyltransferase-geranylgeranyltransferase-I inhibitors as potential cancer chemotherapeutic agents.
S.J.deSolms, T.M.Ciccarone, S.C.MacTough, A.W.Shaw, C.A.Buser, M.Ellis-Hutchings, C.Fernandes, K.A.Hamilton, H.E.Huber, N.E.Kohl, R.B.Lobell, R.G.Robinson, N.N.Tsou, E.S.Walsh, S.L.Graham, L.S.Beese, J.S.Taylor.

ABSTRACT

A series of novel diaryl ether lactams have been identified as very potent dual inhibitors of protein farnesyltransferase (FTase) and protein geranylgeranyltransferase I (GGTase-I), enzymes involved in the prenylation of Ras. The structure of the complex formed between one of these compounds and FTase has been determined by X-ray crystallography. These compounds are the first reported to inhibit the prenylation of the important oncogene Ki-Ras4B in vivo. Unfortunately, doses sufficient to achieve this endpoint were rapidly lethal.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21440964

Y.Qiao, J.Gao, Y.Qiu, L.Wu, F.Guo, K.K.Lo, and D.Li (2011).
Design, synthesis, and characterization of piperazinedione-based dual protein inhibitors for both farnesyltransferase and geranylgeranyltransferase-I.

Eur J Med Chem, 46, 2264-2273.

20308544

M.Liu, A.K.Sjogren, C.Karlsson, M.X.Ibrahim, K.M.Andersson, F.J.Olofsson, A.M.Wahlstrom, M.Dalin, H.Yu, Z.Chen, S.H.Yang, S.G.Young, and M.O.Bergo (2010).
Targeting the protein prenyltransferases efficiently reduces tumor development in mice with K-RAS-induced lung cancer.

Proc Natl Acad Sci U S A, 107, 6471-6476.

17004104

D.R.Budman, J.Tai, and A.Calabro (2007).
Fluvastatin enhancement of trastuzumab and classical cytotoxic agents in defined breast cancer cell lines in vitro.

Breast Cancer Res Treat, 104, 93.

17192846

M.Caraglia, M.Marra, C.Leonetti, G.Meo, A.M.D'Alessandro, A.Baldi, D.Santini, G.Tonini, R.Bertieri, G.Zupi, A.Budillon, and A.Abbruzzese (2007).
R115777 (Zarnestra)/Zoledronic acid (Zometa) cooperation on inhibition of prostate cancer proliferation is paralleled by Erk/Akt inactivation and reduced Bcl-2 and bad phosphorylation.

J Cell Physiol, 211, 533-543.

16935750

S.T.Weiss, N.R.McIntyre, M.L.McLaughlin, and D.J.Merkler (2006).
The development of molecular clamps as drugs.

Drug Discov Today, 11, 819-824.

15611883

S.F.Sousa, P.A.Fernandes, and M.J.Ramos (2005).
Unraveling the mechanism of the farnesyltransferase enzyme.

J Biol Inorg Chem, 10, 3.

16607571

W.C.Guida, A.D.Hamilton, J.W.Crotty, and S.M.Sebti (2005).
Protein farnesyltransferase: flexible docking studies on inhibitors using computational modeling.

J Comput Aided Mol Des, 19, 871-885.

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.