7apq: Difference between revisions
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<StructureSection load='7apq' size='340' side='right'caption='[[7apq]], [[Resolution|resolution]] 1.09Å' scene=''> | <StructureSection load='7apq' size='340' side='right'caption='[[7apq]], [[Resolution|resolution]] 1.09Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7apq]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7APQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7APQ FirstGlance]. <br> | <table><tr><td colspan='2'>[[7apq]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7APQ OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7APQ FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RQW:(1~{S},5~{S},6~{R})-10-(1,3-benzothiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one'>RQW</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.09Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=RQW:(1~{S},5~{S},6~{R})-10-(1,3-benzothiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one'>RQW</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=7apq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apq OCA], [https://pdbe.org/7apq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7apq RCSB], [https://www.ebi.ac.uk/pdbsum/7apq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7apq ProSAT]</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=7apq FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7apq OCA], [https://pdbe.org/7apq PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7apq RCSB], [https://www.ebi.ac.uk/pdbsum/7apq PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7apq ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | == 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;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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</div> | </div> | ||
<div class="pdbe-citations 7apq" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 7apq" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[FKBP 3D structures|FKBP 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Bracher A]] | |||
[[Category: Bracher | [[Category: Hausch F]] | ||
[[Category: Hausch | [[Category: Kolos MJ]] | ||
[[Category: Kolos | [[Category: Krewald V]] | ||
[[Category: Krewald | [[Category: Merz S]] | ||
[[Category: Merz | [[Category: Meyners C]] | ||
[[Category: Meyners | [[Category: Pomplun S]] | ||
[[Category: Pomplun | [[Category: Purder P]] | ||
[[Category: Purder | [[Category: Riess B]] | ||
[[Category: Riess | [[Category: Voll MA]] | ||
[[Category: Voll | |||
Latest revision as of 15:13, 1 February 2024
The Fk1 domain of FKBP51 in complex with (1S,5S,6R)-10-(benzo[d]thiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-oneThe Fk1 domain of FKBP51 in complex with (1S,5S,6R)-10-(benzo[d]thiazol-6-ylsulfonyl)-5-(methoxymethyl)-3-(pyridin-2-ylmethyl)-3,10-diazabicyclo[4.3.1]decan-2-one
Structural highlights
FunctionFKBP5_HUMAN Interacts with functionally mature heterooligomeric progesterone receptor complexes along with HSP90 and TEBP. Publication Abstract from PubMedMethyl groups can have profound effects in drug discovery but the underlying mechanisms are diverse and incompletely understood. Here we report the stereospecific effect of a single, solvent-exposed methyl group in bicyclic [4.3.1] aza-amides, robustly leading to a 2 to 10-fold increase in binding affinity for FK506-binding proteins (FKBPs). This resulted in the most potent and efficient FKBP ligands known to date. By a combination of co-crystal structures, isothermal titration calorimetry (ITC), density-functional theory (DFT), and 3D reference interaction site model (3D-RISM) calculations we elucidated the origin of the observed affinity boost, which was purely entropically driven and relied on the displacement of a water molecule at the protein-ligand-bulk solvent interface. The best compounds potently occupied FKBPs in cells and enhanced bone morphogenic protein (BMP) signaling. Our results show how subtle manipulation of the solvent network can be used to design atom-efficient ligands for difficult, solvent-exposed binding pockets. Picomolar FKBP inhibitors enabled by a single water-displacing methyl group in bicyclic [4.3.1] aza-amides.,Kolos JM, Pomplun S, Jung S, Riess B, Purder PL, Voll AM, Merz S, Gnatzy M, Geiger TM, Quist-Lokken I, Jatzlau J, Knaus P, Holien T, Bracher A, Meyners C, Czodrowski P, Krewald V, Hausch F Chem Sci. 2021 Nov 3;12(44):14758-14765. doi: 10.1039/d1sc04638a. eCollection, 2021 Nov 17. PMID:34820091[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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