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1ld8

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Revision as of 21:46, 24 January 2018

Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49

Structural highlights

1ld8 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:	1ld7, 1jcq
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

A series of macrocyclic 3-aminopyrrolidinone farnesyltransferase inhibitors (FTIs) has been synthesized. Compared with previously described linear 3-aminopyrrolidinone FTIs such as compound 1, macrocycles such as 49 combined improved pharmacokinetic properties with a reduced potential for side effects. In dogs, oral bioavailability was good to excellent, and increases in plasma half-life were due to attenuated clearance. It was observed that in vivo clearance correlated with the flexibility of the molecules and this concept proved useful in the design of FTIs that exhibited low clearance, such as FTI 78. X-ray crystal structures of compounds 49 and 66 complexed with farnesyltransferase (FTase)-farnesyl diphosphate (FPP) were determined, and they provide details of the key interactions in such ternary complexes. Optimization of this 3-aminopyrrolidinone series of compounds led to significant increases in potency, providing 83 and 85, the most potent inhibitors of FTase in cells described to date.

3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency.,Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, Zartman CB J Med Chem. 2002 Jun 6;45(12):2388-409. PMID:12036349^[1]

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

References

↑ Bell IM, Gallicchio SN, Abrams M, Beese LS, Beshore DC, Bhimnathwala H, Bogusky MJ, Buser CA, Culberson JC, Davide J, Ellis-Hutchings M, Fernandes C, Gibbs JB, Graham SL, Hamilton KA, Hartman GD, Heimbrook DC, Homnick CF, Huber HE, Huff JR, Kassahun K, Koblan KS, Kohl NE, Lobell RB, Lynch JJ Jr, Robinson R, Rodrigues AD, Taylor JS, Walsh ES, Williams TM, Zartman CB. 3-Aminopyrrolidinone farnesyltransferase inhibitors: design of macrocyclic compounds with improved pharmacokinetics and excellent cell potency. J Med Chem. 2002 Jun 6;45(12):2388-409. PMID:12036349

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/1ld8"

@@ Line 1: / Line 1: @@
 ==Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49==
 <StructureSection load='1ld8' size='340' side='right' caption='[[1ld8]], [[Resolution|resolution]] 1.80&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=ACY:ACETIC+ACID'>ACY</scene>, <scene name='pdbligand=FPP:FARNESYL+DIPHOSPHATE'>FPP</scene>, <scene name='pdbligand=SUC:SUCROSE'>SUC</scene>, <scene name='pdbligand=U49:(20S)-19,20,21,22-TETRAHYDRO-19-OXO-5H-18,20-ETHANO-12,14-ETHENO-6,10-METHENO-18H-BENZ[D]IMIDAZO[4,3-K][1,6,9,12]OXATRIAZA-CYCLOOCTADECOSINE-9-CARBONITRILE'>U49</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">[[1ld7|1ld7]], [[1jcq|1jcq]]</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=1ld8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ld8 OCA], [http://pdbe.org/1ld8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ld8 RCSB], [http://www.ebi.ac.uk/pdbsum/1ld8 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=1ld8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ld8 OCA], [http://pdbe.org/1ld8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ld8 RCSB], [http://www.ebi.ac.uk/pdbsum/1ld8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ld8 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/ld/1ld8_consurf.spt"</scriptWhenChecked>
+    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/ld/1ld8_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 1ld8" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Farnesyltransferase|Farnesyltransferase]]
 == References ==
 <references/>

1ld8

From Proteopedia

Revision as of 21:46, 24 January 2018

Co-crystal structure of Human Farnesyltransferase with farnesyldiphosphate and inhibitor compound 49

Structural highlights

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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