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==Aryl Tetrahydrophyridine Inhbitors of Farnesyltranferase: Glycine, Phenylalanine and Histidine Derivatives==
==Aryl Tetrahydrophyridine Inhbitors of Farnesyltranferase: Glycine, Phenylalanine and Histidine Derivatives==
<StructureSection load='1n95' size='340' side='right' caption='[[1n95]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
<StructureSection load='1n95' size='340' side='right'caption='[[1n95]], [[Resolution|resolution]] 2.30&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[1n95]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Buffalo_rat Buffalo rat]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1N95 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1N95 FirstGlance]. <br>
<table><tr><td colspan='2'>[[1n95]] 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=1N95 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1N95 FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=FTH:1-[2-(4-CYANO-BENZYLAMINO)-3-(3-METHYL-3H-IMIDAZOL-4-YL)-PROPIONYL]-5-NAPHTHALEN-1-YL-1,2,3,6-TETRAHYDRO-PYRIDINE-4-CARBONITRILE'>FTH</scene>, <scene name='pdbligand=HFP:ALPHA-HYDROXYFARNESYLPHOSPHONIC+ACID'>HFP</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
</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>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1n94|1n94]], [[1n9a|1n9a]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=FTH:1-[2-(4-CYANO-BENZYLAMINO)-3-(3-METHYL-3H-IMIDAZOL-4-YL)-PROPIONYL]-5-NAPHTHALEN-1-YL-1,2,3,6-TETRAHYDRO-PYRIDINE-4-CARBONITRILE'>FTH</scene>, <scene name='pdbligand=HFP:ALPHA-HYDROXYFARNESYLPHOSPHONIC+ACID'>HFP</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1n95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1n95 OCA], [http://pdbe.org/1n95 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1n95 RCSB], [http://www.ebi.ac.uk/pdbsum/1n95 PDBsum]</span></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=1n95 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1n95 OCA], [https://pdbe.org/1n95 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1n95 RCSB], [https://www.ebi.ac.uk/pdbsum/1n95 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1n95 ProSAT]</span></td></tr>
</table>
</table>
== Function ==
== Function ==
[[http://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). [[http://www.uniprot.org/uniprot/FNTB_RAT FNTB_RAT]] 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.  
[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 ==
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
Check<jmol>
   <jmolCheckbox>
   <jmolCheckbox>
     <scriptWhenChecked>select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n9/1n95_consurf.spt"</scriptWhenChecked>
     <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/n9/1n95_consurf.spt"</scriptWhenChecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
     <text>to colour the structure by Evolutionary Conservation</text>
     <text>to colour the structure by Evolutionary Conservation</text>
Line 19: Line 20:
</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=1n95 ConSurf].
</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=1n95 ConSurf].
<div style="clear:both"></div>
<div style="clear:both"></div>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Inhibitors of farnesyltransferase are effective against a variety of tumors in mouse models of cancer. Clinical trials to evaluate these agents in humans are ongoing. In our effort to develop new farnesyltransferase inhibitors, we have discovered a series of aryl tetrahydropyridines that incorporate substituted glycine, phenylalanine and histidine residues. The design, synthesis, SAR and biological properties of these compounds will be discussed.
Aryl tetrahydropyridine inhibitors of farnesyltransferase: glycine, phenylalanine and histidine derivatives.,Gwaltney SL 2nd, O'Connor SJ, Nelson LT, Sullivan GM, Imade H, Wang W, Hasvold L, Li Q, Cohen J, Gu WZ, Tahir SK, Bauch J, Marsh K, Ng SC, Frost DJ, Zhang H, Muchmore S, Jakob CG, Stoll V, Hutchins C, Rosenberg SH, Sham HL Bioorg Med Chem Lett. 2003 Apr 7;13(7):1359-62. PMID:12657282<ref>PMID:12657282</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 1n95" style="background-color:#fffaf0;"></div>


==See Also==
==See Also==
*[[Farnesyltransferase|Farnesyltransferase]]
*[[Farnesyltransferase 3D structures|Farnesyltransferase 3D structures]]
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Buffalo rat]]
[[Category: Large Structures]]
[[Category: Cohen, J]]
[[Category: Rattus norvegicus]]
[[Category: Conner, S J.O]]
[[Category: Cohen J]]
[[Category: Gu, W Z]]
[[Category: Gu WZ]]
[[Category: Hasvold, L]]
[[Category: Gwaltney II SL]]
[[Category: II, S L.Gwaltney]]
[[Category: Hasvold L]]
[[Category: Imade, H]]
[[Category: Imade H]]
[[Category: Li, Q]]
[[Category: Li Q]]
[[Category: Nelson, L T]]
[[Category: Nelson LT]]
[[Category: Sullivan, G M]]
[[Category: O'Conner SJ]]
[[Category: Wang, W]]
[[Category: Sullivan GM]]
[[Category: Farnesyltransferase]]
[[Category: Wang W]]
[[Category: Histidine tetrahydropyridine]]
[[Category: Prenyltransferase]]
[[Category: Transferase]]

Latest revision as of 10:54, 14 February 2024

Aryl Tetrahydrophyridine Inhbitors of Farnesyltranferase: Glycine, Phenylalanine and Histidine DerivativesAryl Tetrahydrophyridine Inhbitors of Farnesyltranferase: Glycine, Phenylalanine and Histidine Derivatives

Structural highlights

1n95 is a 2 chain structure with sequence from Rattus norvegicus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.3Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

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

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

See Also

1n95, resolution 2.30Å

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