7a6x: Difference between revisions
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==Structure of the FKBP51FK1 domain in complex with the macrocyclic SAFit analogue 56== | ==Structure of the FKBP51FK1 domain in complex with the macrocyclic SAFit analogue 56== | ||
<StructureSection load='7a6x' size='340' side='right'caption='[[7a6x]]' scene=''> | <StructureSection load='7a6x' size='340' side='right'caption='[[7a6x]], [[Resolution|resolution]] 1.67Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A6X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A6X FirstGlance]. <br> | <table><tr><td colspan='2'>[[7a6x]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7A6X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7A6X FirstGlance]. <br> | ||
</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=7a6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a6x OCA], [https://pdbe.org/7a6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a6x RCSB], [https://www.ebi.ac.uk/pdbsum/7a6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a6x ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=R3B:(2S,9S,12R)-2-cyclohexyl-12-[2-(3,4-dimethoxyphenyl)ethyl]-24,27-dimethoxy-11,18,22-trioxa-4-azatetracyclo[21.2.2.113,17.04,9]octacosa-1(25),13(28),14,16,23,26-hexaene-3,10-dione'>R3B</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">FKBP5, AIG6, FKBP51 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Peptidylprolyl_isomerase Peptidylprolyl isomerase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=7a6x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7a6x OCA], [https://pdbe.org/7a6x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7a6x RCSB], [https://www.ebi.ac.uk/pdbsum/7a6x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7a6x ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Function == | |||
[[https://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 protein 51 (FKBP51) emerged as a key player in several diseases like stress-related disorders, chronic pain, and obesity. Linear analogues of FK506 called SAFit were shown to be highly selective for FKBP51 over its closest homologue FKBP52, allowing the proof-of-concept studies in animal models. Here, we designed and synthesized the first macrocyclic FKBP51-selective ligands to stabilize the active conformation. All macrocycles retained full FKBP51 affinity and selectivity over FKBP52 and the incorporation of polar functionalities further enhanced affinity. Six high-resolution crystal structures of macrocyclic inhibitors in complex with FKBP51 confirmed the desired selectivity-enabling binding mode. Our results show that macrocyclization is a viable strategy to target the shallow FKBP51 binding site selectively. | |||
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors.,Bauder M, Meyners C, Purder PL, Merz S, Sugiarto WO, Voll AM, Heymann T, Hausch F J Med Chem. 2021 Mar 5. doi: 10.1021/acs.jmedchem.0c02195. PMID:33666419<ref>PMID:33666419</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7a6x" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bauder M]] | [[Category: Peptidylprolyl isomerase]] | ||
[[Category: Hausch F]] | [[Category: Bauder, M]] | ||
[[Category: Heymann T]] | [[Category: Hausch, F]] | ||
[[Category: Merz S]] | [[Category: Heymann, T]] | ||
[[Category: Meyners C]] | [[Category: Merz, S]] | ||
[[Category: Purder P]] | [[Category: Meyners, C]] | ||
[[Category: Voll A]] | [[Category: Purder, P]] | ||
[[Category: Voll, A]] | |||
[[Category: Complex]] | |||
[[Category: Fkbp]] | |||
[[Category: Inhibitor]] | |||
[[Category: Isomerase]] | |||
[[Category: Safit]] | |||