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1o1r

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[[Image:1o1r.jpg|left|200px]]<br /><applet load="1o1r" size="350" color="white" frame="true" align="right" spinBox="true"
 
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caption="1o1r, resolution 2.3&Aring;" />
 
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'''Structure of FPT bound to GGPP'''<br />
 
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==Overview==
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==Structure of FPT bound to GGPP==
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Protein farnesyl transferase (PFTase) catalyzes the reaction between farnesyl diphosphate and a protein substrate to form a thioether-linked prenylated protein. The fact that many prenylated proteins are involved in signaling processes has generated considerable interest in protein prenyl transferases as possible anticancer targets. While considerable progress has been made in understanding how prenyl transferases distinguish between related target proteins, the rules for isoprenoid discrimination by these enzymes are less well understood. To clarify how PFTase discriminates between FPP and larger prenyl diphosphates, we have examined the interactions between the enzyme and several isoprenoid analogues, GGPP, and the farnesylated peptide product using a combination of biochemical and structural methods. Two photoactive isoprenoid analogues were shown to inhibit yeast PFTase with K(I) values as low as 45 nM. Crystallographic analysis of one of these analogues bound to PFTase reveals that the diphosphate moiety and the two isoprene units bind in the same positions occupied by the corresponding atoms in FPP when bound to PFTase. However, the benzophenone group protrudes into the acceptor protein binding site and prevents the binding of the second (protein) substrate. Crystallographic analysis of geranylgeranyl diphosphate bound to PFTase shows that the terminal two isoprene units and diphosphate group of the molecule map to the corresponding atoms in FPP; however, the first and second isoprene units bulge away from the acceptor protein binding site. Comparison of the GGPP binding mode with the binding of the farnesylated peptide product suggests that the bulkier isoprenoid cannot rearrange to convert to product without unfavorable steric interactions with the acceptor protein. Taken together, these data do not support the "molecular ruler hypotheses". Instead, we propose a "second site exclusion model" in which PFTase binds larger isoprenoids in a fashion that prevents the subsequent productive binding of the acceptor protein or its conversion to product.
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<StructureSection load='1o1r' size='340' side='right'caption='[[1o1r]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1o1r]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1O1R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1O1R FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GRG:GERANYLGERANYL+DIPHOSPHATE'>GRG</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1o1r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1o1r OCA], [https://pdbe.org/1o1r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1o1r RCSB], [https://www.ebi.ac.uk/pdbsum/1o1r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1o1r ProSAT]</span></td></tr>
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</table>
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== Function ==
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[https://www.uniprot.org/uniprot/FNTA_RAT FNTA_RAT] 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).
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o1/1o1r_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1o1r ConSurf].
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<div style="clear:both"></div>
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==About this Structure==
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==See Also==
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1O1R is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus] with <scene name='pdbligand=ZN:'>ZN</scene> and <scene name='pdbligand=GRG:'>GRG</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1O1R OCA].
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*[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]]
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__TOC__
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==Reference==
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</StructureSection>
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Biochemical and structural studies with prenyl diphosphate analogues provide insights into isoprenoid recognition by protein farnesyl transferase., Turek-Etienne TC, Strickland CL, Distefano MD, Biochemistry. 2003 Apr 8;42(13):3716-24. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12667062 12667062]
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[[Category: Large Structures]]
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[[Category: Protein complex]]
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[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
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[[Category: Distefano, M D.]]
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[[Category: Distefano MD]]
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[[Category: Strickland, C L.]]
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[[Category: Strickland CL]]
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[[Category: Turek-Etienne, T C.]]
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[[Category: Turek-Etienne TC]]
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[[Category: GRG]]
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[[Category: ZN]]
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[[Category: prenyltransferase]]
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[[Category: transferase]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 14:12:22 2008''
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Current revision

Structure of FPT bound to GGPP

PDB ID 1o1r

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