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New page: left|200px<br /> <applet load="1d8d" size="450" color="white" frame="true" align="right" spinBox="true" caption="1d8d, resolution 2.00Å" /> '''CO-CRYSTAL STRUCTUR...
 
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[[Image:1d8d.gif|left|200px]]<br />
<applet load="1d8d" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1d8d, resolution 2.00&Aring;" />
'''CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION'''<br />


==Overview==
==CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION==
Background: The protein farnesyltransferase (FTase) catalyzes addition of, the hydrophobic farnesyl isoprenoid to a cysteine residue fourth from the, C terminus of several protein acceptors that are essential for cellular, signal transduction such as Ras and Rho. This addition is necessary for, the biological function of the modified proteins. The majority of, Ras-related human cancers are associated with oncogenic variants of, K-RasB, which is the highest affinity natural substrate of FTase., Inhibition of FTase causes regression of Ras-mediated tumors in animal, models. Results: We present four ternary complexes of rat FTase, co-crystallized with farnesyl diphosphate analogs and K-Ras4B peptide, substrates. The Ca(1)a(2)X portion of the peptide substrate binds in an, extended conformation in the hydrophobic cavity of FTase and coordinates, the active site zinc ion. These complexes offer the first view of the, polybasic region of the K-Ras4B peptide substrate, which confers the major, enhancement of affinity of this substrate. The polybasic region forms a, type I beta turn and binds along the rim of the hydrophobic cavity., Removal of the catalytically essential zinc ion results in a dramatically, different peptide conformation in which the Ca(1)a(2)X motif adopts a beta, turn. A manganese ion binds to the diphosphate mimic of the farnesyl, diphosphate analog. Conclusions: These ternary complexes provide new, insight into the molecular basis of peptide substrate specificity, and, further define the roles of zinc and magnesium in the prenyltransferase, reaction. Zinc is essential for productive Ca(1)a(2)X peptide binding, suggesting that the beta-turn conformation identified in previous nuclear, magnetic resonance (NMR) studies reflects a state in which the cysteine is, not coordinated to the zinc ion. The structural information presented here, should facilitate structure-based design and optimization of inhibitors of, Ca(1)a(2)X protein prenyltransferases.
<StructureSection load='1d8d' size='340' side='right'caption='[[1d8d]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[1d8d]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Rattus_norvegicus Rattus norvegicus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1D8D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1D8D FirstGlance]. <br>
</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&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=FII:[(3,7,11-TRIMETHYL-DODECA-2,6,10-TRIENYLOXYCARBAMOYL)-METHYL]-PHOSPHONIC+ACID'>FII</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1d8d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1d8d OCA], [https://pdbe.org/1d8d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1d8d RCSB], [https://www.ebi.ac.uk/pdbsum/1d8d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1d8d ProSAT]</span></td></tr>
</table>
== Function ==
[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).
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/d8/1d8d_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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=1d8d ConSurf].
<div style="clear:both"></div>


==Disease==
==See Also==
Known diseases associated with this structure: Bladder cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Breast cancer, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Costello syndrome OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Leukemia, acute myelogenous OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Lung cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Noonan syndrome 3 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Pancreatic carcinoma, somatic OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]], Stomach cancer OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=190070 190070]]
*[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]]
 
__TOC__
==About this Structure==
</StructureSection>
1D8D 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 ACT, ZN and FII as [http://en.wikipedia.org/wiki/ligands ligands]. Active as [http://en.wikipedia.org/wiki/Squalene_synthase Squalene synthase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.21 2.5.1.21] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1D8D OCA].
[[Category: Homo sapiens]]
 
[[Category: Large Structures]]
==Reference==
The basis for K-Ras4B binding specificity to protein farnesyltransferase revealed by 2 A resolution ternary complex structures., Long SB, Casey PJ, Beese LS, Structure. 2000 Feb 15;8(2):209-22. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=10673434 10673434]
[[Category: Protein complex]]
[[Category: Rattus norvegicus]]
[[Category: Rattus norvegicus]]
[[Category: Squalene synthase]]
[[Category: Beese LS]]
[[Category: Beese, L.S.]]
[[Category: Casey PJ]]
[[Category: Casey, P.J.]]
[[Category: Long SB]]
[[Category: Long, S.B.]]
[[Category: ACT]]
[[Category: FII]]
[[Category: ZN]]
[[Category: caax]]
[[Category: cancer]]
[[Category: farnesyl transferase]]
[[Category: farnesyltransferase]]
[[Category: ftase]]
[[Category: pft]]
[[Category: pftase]]
[[Category: ras]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 16:30:14 2007''

Latest revision as of 06:50, 7 February 2024

CO-CRYSTAL STRUCTURE OF RAT PROTEIN FARNESYLTRANSFERASE COMPLEXED WITH A K-RAS4B PEPTIDE SUBSTRATE AND FPP ANALOG AT 2.0A RESOLUTION

1d8d, resolution 2.00Å

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