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1jcq

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Revision as of 08:49, 17 January 2018

CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750

Structural highlights

1jcq is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, , , ,
Related:	1jcr, 1jcs, 1d8d, 1ft1
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[FNTA_HUMAN] Catalyzes the transfer of a farnesyl or geranyl-geranyl moiety from farnesyl or geranyl-geranyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins having the C-terminal sequence Cys-aliphatic-aliphatic-X. The alpha subunit is thought to participate in a stable complex with the substrate. The beta subunit binds the peptide substrate. Through RAC1 prenylation and activation may positively regulate neuromuscular junction development downstream of MUSK (By similarity). [FNTB_HUMAN] Catalyzes the transfer of a farnesyl moiety from farnesyl pyrophosphate to a cysteine at the fourth position from the C-terminus of several proteins. The beta subunit is responsible for peptide-binding.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily. Farnesylation is essential both for normal functioning of these proteins, and for the transforming activity of oncogenic mutants. Consequently FTase is an important target for anti-cancer therapeutics. Several FTase inhibitors are currently undergoing clinical trials for cancer treatment. Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue. These structures reveal the structural mechanism of FTase inhibition. Some CaaX tetrapeptide inhibitors are not farnesylated, and are more effective inhibitors than farnesylated CaaX tetrapeptides. CVFM and L-739,750 are not farnesylated, because these inhibitors bind in a conformation that is distinct from the TKCVFM hexapeptide substrate. This non-substrate binding mode is stabilized by an ion pair between the peptide N terminus and the alpha-phosphate of the FPP substrate. Conformational mapping calculations reveal the basis for the sequence specificity in the third position of the CaaX motif that determines whether a tetrapeptide is a substrate or non-substrate. The presence of beta-branched amino acids in this position prevents formation of the non-substrate conformation; all other aliphatic amino acids in this position are predicted to form the non-substrate conformation, provided their N terminus is available to bind to the FPP alpha-phosphate. These results may facilitate further development of FTase inhibitors.

The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.,Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12948-53. Epub 2001 Oct 30. PMID:11687658^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Long SB, Hancock PJ, Kral AM, Hellinga HW, Beese LS. The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics. Proc Natl Acad Sci U S A. 2001 Nov 6;98(23):12948-53. Epub 2001 Oct 30. PMID:11687658 doi:10.1073/pnas.241407898

1 Structural highlights
2 Function
3 Evolutionary Conservation
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1jcq"

@@ Line 1: / Line 1: @@
 ==CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750==
 <StructureSection load='1jcq' size='340' side='right' caption='[[1jcq]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
@@ Line 5: / Line 6: @@
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=739:2(S)-{2(S)-[2(R)-AMINO-3-MERCAPTO]PROPYLAMINO-3(S)-METHYL}PENTYLOXY-3-PHENYLPROPIONYLMETHIONINE+SULFONE'>739</scene>, <scene name='pdbligand=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1jcr|1jcr]], [[1jcs|1jcs]], [[1d8d|1d8d]], [[1ft1|1ft1]]</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1jcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jcq OCA], [http://pdbe.org/1jcq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1jcq RCSB], [http://www.ebi.ac.uk/pdbsum/1jcq PDBsum]</span></td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1jcq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1jcq OCA], [http://pdbe.org/1jcq PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1jcq RCSB], [http://www.ebi.ac.uk/pdbsum/1jcq PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1jcq ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 13: / Line 14: @@
 Check<jmol>
   <jmolCheckbox>
-    <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jc/1jcq_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/jc/1jcq_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
@@ Line 28: / Line 29: @@
 </div>
 <div class="pdbe-citations 1jcq" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Farnesyltransferase|Farnesyltransferase]]
 == References ==
 <references/>

1jcq

From Proteopedia

Revision as of 08:49, 17 January 2018

CRYSTAL STRUCTURE OF HUMAN PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH FARNESYL DIPHOSPHATE AND THE PEPTIDOMIMETIC INHIBITOR L-739,750

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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