4tw8

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==The Fk1-Fk2 domains of FKBP52 in complex with iFit-FL==
==The Fk1-Fk2 domains of FKBP52 in complex with iFit-FL==
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<StructureSection load='4tw8' size='340' side='right' caption='[[4tw8]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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<StructureSection load='4tw8' size='340' side='right'caption='[[4tw8]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4tw8]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TW8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TW8 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4tw8]] is a 2 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=4TW8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TW8 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=37M:2-(5-{[({3-[(1R)-1-[({(2S)-1-[(2S)-2-[(1S)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidin-2-yl}carbonyl)oxy]-3-(3,4-dimethoxyphenyl)propyl]phenoxy}acetyl)amino]methyl}-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic+acid'>37M</scene></td></tr>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.003&#8491;</td></tr>
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<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>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=37M:2-(5-{[({3-[(1R)-1-[({(2S)-1-[(2S)-2-[(1S)-cyclohex-2-en-1-yl]-2-(3,4,5-trimethoxyphenyl)acetyl]piperidin-2-yl}carbonyl)oxy]-3-(3,4-dimethoxyphenyl)propyl]phenoxy}acetyl)amino]methyl}-6-hydroxy-3-oxo-3H-xanthen-9-yl)benzoic+acid'>37M</scene></td></tr>
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<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=4tw8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tw8 OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4tw8 RCSB], [http://www.ebi.ac.uk/pdbsum/4tw8 PDBsum]</span></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tw8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tw8 OCA], [https://pdbe.org/4tw8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tw8 RCSB], [https://www.ebi.ac.uk/pdbsum/4tw8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tw8 ProSAT]</span></td></tr>
</table>
</table>
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== Function ==
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[https://www.uniprot.org/uniprot/FKBP4_HUMAN FKBP4_HUMAN] Immunophilin protein with PPIase and co-chaperone activities (By similarity). Component of unligated steroid receptors heterocomplexes through interaction with heat-shock protein 90 (HSP90). May play a role in the intracellular trafficking of heterooligomeric forms of steroid hormone receptors between cytoplasm and nuclear compartments (By similarity). The isomerase activity controls neuronal growth cones via regulation of TRPC1 channel opening. Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU ability to promote microtubule assembly. May have a protective role against oxidative stress in mitochondria.<ref>PMID:1279700</ref> <ref>PMID:1376003</ref> <ref>PMID:2378870</ref> <ref>PMID:19945390</ref> <ref>PMID:21730050</ref>
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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The human Hsp90 co-chaperone FKBP52 belongs to the family of FK506-binding proteins, which act as peptidyl-prolyl isomerases. FKBP52 specifically enhances the signaling of steroid hormone receptors, modulates ion channels and regulates neuronal outgrowth dynamics. In turn, small-molecule ligands of FKBP52 have been suggested as potential neurotrophic or anti-prostate cancer agents. The usefulness of available ligands is however limited by a lack of selectivity. The immunophilin FKBP52 is composed of three domains, an FK506-binding domain with peptidyl-prolyl isomerase activity, an FKBP-like domain of unknown function and a TPR-clamp domain, which recognizes the C-terminal peptide of Hsp90 with high affinity. The herein reported crystal structures of FKBP52 reveal that the short linker connecting the FK506-binding domain and the FKBP-like domain acts as a flexible hinge. This enhanced flexibility and its modulation by phosphorylation might explain some of the functional antagonism between the closely related homologs FKBP51 and FKBP52. We further present two co-crystal structures of FKBP52 in complex with the prototypic ligand FK506 and a synthetic analog thereof. These structures revealed the molecular interactions in great detail, which enabled in-depth comparison with the corresponding complexes of the other cytosolic FKBPs, FKBP51 and FKBP12. The observed subtle differences provide crucial insights for the rational design of ligands with improved selectivity for FKBP52.
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The FK506-binding protein 51 (FKBP51, encoded by the FKBP5 gene) is an established risk factor for stress-related psychiatric disorders such as major depression. Drug discovery for FKBP51 has been hampered by the inability to pharmacologically differentiate against the structurally similar but functional opposing homolog FKBP52, and all known FKBP ligands are unselective. Here, we report the discovery of the potent and highly selective inhibitors of FKBP51, SAFit1 and SAFit2. This new class of ligands achieves selectivity for FKBP51 by an induced-fit mechanism that is much less favorable for FKBP52. By using these ligands, we demonstrate that selective inhibition of FKBP51 enhances neurite elongation in neuronal cultures and improves neuroendocrine feedback and stress-coping behavior in mice. Our findings provide the structural and functional basis for the development of mechanistically new antidepressants.
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Crystal Structures of the Free and Ligand-Bound FK1-FK2 Domain Segment of FKBP52 Reveal a Flexible Inter-Domain Hinge.,Bracher A, Kozany C, Hahle A, Wild P, Zacharias M, Hausch F J Mol Biol. 2013 Aug 8. pii: S0022-2836(13)00502-0. doi:, 10.1016/j.jmb.2013.07.041. PMID:23933011<ref>PMID:23933011</ref>
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Selective inhibitors of the FK506-binding protein 51 by induced fit.,Gaali S, Kirschner A, Cuboni S, Hartmann J, Kozany C, Balsevich G, Namendorf C, Fernandez-Vizarra P, Sippel C, Zannas AS, Draenert R, Binder EB, Almeida OF, Ruhter G, Uhr M, Schmidt MV, Touma C, Bracher A, Hausch F Nat Chem Biol. 2014 Dec 1. doi: 10.1038/nchembio.1699. PMID:25436518<ref>PMID:25436518</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
</div>
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<div class="pdbe-citations 4tw8" style="background-color:#fffaf0;"></div>
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==See Also==
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*[[FKBP 3D structures|FKBP 3D structures]]
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Peptidylprolyl isomerase]]
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[[Category: Homo sapiens]]
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[[Category: Almeida, O F.X]]
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[[Category: Large Structures]]
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[[Category: Balsevich, G]]
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[[Category: Almeida OFX]]
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[[Category: Bracher, A]]
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[[Category: Balsevich G]]
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[[Category: Cuboni, S]]
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[[Category: Bracher A]]
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[[Category: Fernandez-Vizarra, P]]
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[[Category: Cuboni S]]
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[[Category: Gaali, S]]
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[[Category: Fernandez-Vizarra P]]
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[[Category: Hartmann, J]]
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[[Category: Gaali S]]
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[[Category: Hausch, F]]
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[[Category: Hartmann J]]
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[[Category: Kirschner, A]]
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[[Category: Hausch F]]
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[[Category: Kozany, C]]
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[[Category: Kirschner A]]
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[[Category: Namendorf, C]]
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[[Category: Kozany C]]
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[[Category: Ruehter, G]]
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[[Category: Namendorf C]]
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[[Category: Schmidt, M V]]
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[[Category: Ruehter G]]
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[[Category: Touma, C]]
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[[Category: Schmidt MV]]
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[[Category: Uhr, M]]
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[[Category: Touma C]]
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[[Category: Fk-506 binding domain]]
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[[Category: Uhr M]]
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[[Category: Hsp90 cochaperone]]
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[[Category: Immunophiline]]
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[[Category: Isomerase]]
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[[Category: Ligand selectivity]]
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[[Category: Peptidyl-prolyl isomerase]]
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Current revision

The Fk1-Fk2 domains of FKBP52 in complex with iFit-FL

PDB ID 4tw8

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