PDBsum entry 3dpy

Transferase

PDB id: 3dpy

Contents

Protein chains

323 a.a. *

407 a.a. *

Ligands

VAL-ILE-MET

FPP

ACY

Metals

_ZN

Waters ×60

* Residue conservation analysis

PDB id:

3dpy

Name:

Transferase

Title:

Protein farnesyltransferase complexed with fpp and caged tkcvim substrate

Structure:

Protein farnesyltransferase/geranylgeranyltransferase type- 1 subunit alpha. Chain: a. Synonym: caax farnesyltransferase subunit alpha, ras proteins prenyltransferase alpha, ftase-alpha, type i protein geranyl- geranyltransferase subunit alpha, ggtase-i-alpha. Engineered: yes. Protein farnesyltransferase subunit beta. Chain: b.

Source:

Rattus norvegicus. Brown rat,rat,rats. Organism_taxid: 10116. Gene: fnta. Expressed in: spodoptera frugiperda. Expression_system_taxid: 7108. Gene: fntb. Synthetic: yes. Other_details: synthesized peptide

Resolution:

2.70Å R-factor: 0.217 R-free: 0.253

Authors:

M.A.Hast,L.S.Beese

Key ref:

A.J.DeGraw et al. (2008). Caged protein prenyltransferase substrates: tools for understanding protein prenylation. Chem Biol Drug Des, 72, 171-181. PubMed id: 18844669

Date:

09-Jul-08 Release date: 30-Sep-08

Protein chain

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

Seq: 377 a.a.

Struc: 323 a.a.

Protein chain

Q02293  (FNTB_RAT) -  Protein farnesyltransferase subunit beta from Rattus norvegicus

Seq: 437 a.a.

Struc: 407 a.a.

Enzyme reactions

• Enzyme class 1: Chains A, B: E.C.2.5.1.58 - protein farnesyltransferase.
• 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.
• 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

Chem Biol Drug Des 72:171-181 (2008)

PubMed id: 18844669

Caged protein prenyltransferase substrates: tools for understanding protein prenylation.

A.J.DeGraw, M.A.Hast, J.Xu, D.Mullen, L.S.Beese, G.Barany, M.D.Distefano.

ABSTRACT

Originally designed to block the prenylation of oncogenic Ras, inhibitors of protein farnesyltransferase currently in preclinical and clinical trials are showing efficacy in cancers with normal Ras. Blocking protein prenylation has also shown promise in the treatment of malaria, Chagas disease and progeria syndrome. A better understanding of the mechanism, targets and in vivo consequences of protein prenylation are needed to elucidate the mode of action of current PFTase (Protein Farnesyltransferase) inhibitors and to create more potent and selective compounds. Caged enzyme substrates are useful tools for understanding enzyme mechanism and biological function. Reported here is the synthesis and characterization of caged substrates of PFTase. The caged isoprenoid diphosphates are poor substrates prior to photolysis. The caged CAAX peptide is a true catalytically caged substrate of PFTase in that it is to not a substrate, yet is able to bind to the enzyme as established by inhibition studies and X-ray crystallography. Irradiation of the caged molecules with 350 nm light readily releases their cognate substrate and their photolysis products are benign. These properties highlight the utility of those analogs towards a variety of in vitro and in vivo applications.