6yf1: Difference between revisions
New page: '''Unreleased structure''' The entry 6yf1 is ON HOLD Authors: Kallen, J. Description: FKBP12 in complex with the BMP potentiator compound 8 at 1.12A resolution [[Category: Unreleased S... |
No edit summary |
||
| (5 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
==FKBP12 in complex with the BMP potentiator compound 8 at 1.12A resolution== | |||
<StructureSection load='6yf1' size='340' side='right'caption='[[6yf1]], [[Resolution|resolution]] 1.12Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6yf1]] 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=6YF1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YF1 FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.12Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=OP8:(1aR,3R,5S,6R,7S,9R,10R,17aS,20S,21R,22S,25R,25aR)-25-Ethyl-10,22-dihydroxy-20-{(1E)-1-[(1R,3R,4R)-4-hydroxy-3-methoxycyclohexyl]prop-1-en-2-yl}-5,7-dimethoxy-1a,3,9,21-tetramethyloctadecahydro-2H-6,10-epoxyoxireno[p]pyrido[2,1-c][1,4]oxazacyclotricosine-11,12,18,24(1aH,14H)-tetrone'>OP8</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=6yf1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yf1 OCA], [https://pdbe.org/6yf1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yf1 RCSB], [https://www.ebi.ac.uk/pdbsum/6yf1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yf1 ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/FKB1A_HUMAN FKB1A_HUMAN] Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.<ref>PMID:9233797</ref> <ref>PMID:16720724</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Acute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling. | |||
Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury.,Larraufie MH, Gao X, Xia X, Devine PJ, Kallen J, Liu D, Michaud G, Harsch A, Savage N, Ding J, Tan K, Mihalic M, Roggo S, Canham SM, Bushell SM, Krastel P, Gao J, Izaac A, Altinoglu E, Lustenberger P, Salcius M, Harbinski F, Williams ET, Zeng L, Loureiro J, Cong F, Fryer CJ, Klickstein L, Tallarico JA, Jain RK, Rothman DM, Wang S Cell Chem Biol. 2021 Apr 17. pii: S2451-9456(21)00156-2. doi:, 10.1016/j.chembiol.2021.04.001. PMID:33894161<ref>PMID:33894161</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Kallen | <div class="pdbe-citations 6yf1" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[FKBP 3D structures|FKBP 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Kallen J]] | |||
Latest revision as of 16:25, 24 January 2024
FKBP12 in complex with the BMP potentiator compound 8 at 1.12A resolutionFKBP12 in complex with the BMP potentiator compound 8 at 1.12A resolution
Structural highlights
FunctionFKB1A_HUMAN Keeps in an inactive conformation TGFBR1, the TGF-beta type I serine/threonine kinase receptor, preventing TGF-beta receptor activation in absence of ligand. Recruites SMAD7 to ACVR1B which prevents the association of SMAD2 and SMAD3 with the activin receptor complex, thereby blocking the activin signal. May modulate the RYR1 calcium channel activity. PPIases accelerate the folding of proteins. It catalyzes the cis-trans isomerization of proline imidic peptide bonds in oligopeptides.[1] [2] Publication Abstract from PubMedAcute kidney injury (AKI) is a life-threatening disease with no known curative or preventive therapies. Data from multiple animal models and human studies have linked dysregulation of bone morphogenetic protein (BMP) signaling to AKI. Small molecules that potentiate endogenous BMP signaling should have a beneficial effect in AKI. We performed a high-throughput phenotypic screen and identified a series of FK506 analogs that act as potent BMP potentiators by sequestering FKBP12 from BMP type I receptors. We further showed that calcineurin inhibition was not required for this activity. We identified a calcineurin-sparing FK506 analog oxtFK through late-stage functionalization and structure-guided design. OxtFK demonstrated an improved safety profile in vivo relative to FK506. OxtFK stimulated BMP signaling in vitro and in vivo and protected the kidneys in an AKI mouse model, making it a promising candidate for future development as a first-in-class therapeutic for diseases with dysregulated BMP signaling. Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury.,Larraufie MH, Gao X, Xia X, Devine PJ, Kallen J, Liu D, Michaud G, Harsch A, Savage N, Ding J, Tan K, Mihalic M, Roggo S, Canham SM, Bushell SM, Krastel P, Gao J, Izaac A, Altinoglu E, Lustenberger P, Salcius M, Harbinski F, Williams ET, Zeng L, Loureiro J, Cong F, Fryer CJ, Klickstein L, Tallarico JA, Jain RK, Rothman DM, Wang S Cell Chem Biol. 2021 Apr 17. pii: S2451-9456(21)00156-2. doi:, 10.1016/j.chembiol.2021.04.001. PMID:33894161[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||