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[[ | ==Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52: Complex of FKBP51 with 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1R,2S)-2-ethyl-1-hydroxy-cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid from cocrystallization== | ||
<StructureSection load='4drp' size='340' side='right' caption='[[4drp]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[4drp]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4DRP OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4DRP FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0MD:{3-[(1R)-3-(3,4-DIMETHOXYPHENYL)-1-({[(2S)-1-{[(1R,2S)-2-ETHYL-1-HYDROXYCYCLOHEXYL](OXO)ACETYL}PIPERIDIN-2-YL]CARBONYL}OXY)PROPYL]PHENOXY}ACETIC+ACID'>0MD</scene></td></tr> | |||
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4drk|4drk]], [[4drm|4drm]], [[4drn|4drn]], [[4dro|4dro]], [[4drq|4drq]]</td></tr> | |||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AIG6, FKBP5, FKBP51 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=5.2.1.8 5.2.1.8] </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=4drp FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4drp OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4drp RCSB], [http://www.ebi.ac.uk/pdbsum/4drp PDBsum]</span></td></tr> | |||
</table> | |||
== Function == | |||
[[http://www.uniprot.org/uniprot/FKBP5_HUMAN FKBP5_HUMAN]] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography. | |||
Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52.,Gopalakrishnan R, Kozany C, Gaali S, Kress C, Hoogeland B, Bracher A, Hausch F J Med Chem. 2012 May 10;55(9):4114-22. Epub 2012 Apr 19. PMID:22455444<ref>PMID:22455444</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
==See Also== | |||
*[[FK506 binding protein|FK506 binding protein]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
== | |||
[[ | |||
== | |||
< | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Peptidylprolyl isomerase]] | [[Category: Peptidylprolyl isomerase]] | ||
[[Category: Bracher, A | [[Category: Bracher, A]] | ||
[[Category: Gaali, S | [[Category: Gaali, S]] | ||
[[Category: Gopalakrishnan, R | [[Category: Gopalakrishnan, R]] | ||
[[Category: Hausch, F | [[Category: Hausch, F]] | ||
[[Category: Hoogeland, B | [[Category: Hoogeland, B]] | ||
[[Category: Kozany, C | [[Category: Kozany, C]] | ||
[[Category: Kress, C | [[Category: Kress, C]] | ||
[[Category: Fk-506 binding domain]] | [[Category: Fk-506 binding domain]] | ||
[[Category: Hsp90 cochaperone]] | [[Category: Hsp90 cochaperone]] | ||
Revision as of 22:10, 24 December 2014
Evaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52: Complex of FKBP51 with 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1R,2S)-2-ethyl-1-hydroxy-cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid from cocrystallizationEvaluation of Synthetic FK506 Analogs as Ligands for the FK506-Binding Proteins 51 and 52: Complex of FKBP51 with 2-(3-((R)-3-(3,4-dimethoxyphenyl)-1-((S)-1-(2-((1R,2S)-2-ethyl-1-hydroxy-cyclohexyl)-2-oxoacetyl)piperidine-2-carbonyloxy)propyl)phenoxy)acetic acid from cocrystallization
Structural highlights
Function[FKBP5_HUMAN] Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMedThe FK506-binding proteins (FKBP) 51 and 52 are cochaperones that modulate the signal transduction of steroid hormone receptors. Both proteins have been implicated in prostate cancer. Furthermore, single nucleotide polymorphisms in the gene encoding FKBP51 have been associated with a variety of psychiatric disorders. Rapamycin and FK506 are two macrocyclic natural products that bind to these proteins indiscriminately but with nanomolar affinity. We here report the cocrystal structure of FKBP51 with a simplified alpha-ketoamide analogue derived from FK506 and the first structure-activity relationship analysis for FKBP51 and FKBP52 based on this compound. In particular, the tert-pentyl group of this ligand was systematically replaced by a cyclohexyl ring system, which more closely resembles the pyranose ring in the high-affinity ligands rapamycin and FK506. The interaction with FKBPs was found to be surprisingly tolerant to the stereochemistry of the attached cyclohexyl substituents. The molecular basis for this tolerance was elucidated by X-ray cocrystallography. Evaluation of Synthetic FK506 Analogues as Ligands for the FK506-Binding Proteins 51 and 52.,Gopalakrishnan R, Kozany C, Gaali S, Kress C, Hoogeland B, Bracher A, Hausch F J Med Chem. 2012 May 10;55(9):4114-22. Epub 2012 Apr 19. PMID:22455444[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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