| Structural highlights
Function
[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.[1] [2]
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[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chen YG, Liu F, Massague J. Mechanism of TGFbeta receptor inhibition by FKBP12. EMBO J. 1997 Jul 1;16(13):3866-76. PMID:9233797 doi:10.1093/emboj/16.13.3866
- ↑ Yamaguchi T, Kurisaki A, Yamakawa N, Minakuchi K, Sugino H. FKBP12 functions as an adaptor of the Smad7-Smurf1 complex on activin type I receptor. J Mol Endocrinol. 2006 Jun;36(3):569-79. PMID:16720724 doi:10.1677/jme.1.01966
- ↑ 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. Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury. Cell Chem Biol. 2021 Apr 17. pii: S2451-9456(21)00156-2. doi:, 10.1016/j.chembiol.2021.04.001. PMID:33894161 doi:http://dx.doi.org/10.1016/j.chembiol.2021.04.001
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