7apq
From Proteopedia
(Difference between revisions)
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==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-one== | ==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-one== | ||
| - | <StructureSection load='7apq' size='340' side='right'caption='[[7apq]]' scene=''> | + | <StructureSection load='7apq' size='340' side='right'caption='[[7apq]], [[Resolution|resolution]] 1.09Å' 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=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. 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='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> | + | </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='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=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 == | ||
| + | [[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 == | ||
| + | Methyl 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<ref>PMID:34820091</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 7apq" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Bracher A]] | + | [[Category: Peptidylprolyl isomerase]] |
| - | [[Category: Hausch F]] | + | [[Category: Bracher, A]] |
| - | [[Category: Kolos | + | [[Category: Hausch, F]] |
| - | [[Category: Krewald V]] | + | [[Category: Kolos, M J]] |
| - | [[Category: Merz S]] | + | [[Category: Krewald, V]] |
| - | [[Category: Meyners C]] | + | [[Category: Merz, S]] |
| - | [[Category: Pomplun S]] | + | [[Category: Meyners, C]] |
| - | [[Category: Purder P]] | + | [[Category: Pomplun, S]] |
| - | [[Category: Riess B]] | + | [[Category: Purder, P]] |
| - | [[Category: Voll | + | [[Category: Riess, B]] |
| + | [[Category: Voll, M A]] | ||
| + | [[Category: Conformation analysis]] | ||
| + | [[Category: Density functional calculation]] | ||
| + | [[Category: Fkbp]] | ||
| + | [[Category: Isomerase]] | ||
| + | [[Category: Magic methyl]] | ||
Revision as of 10:02, 8 December 2021
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-one
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