6YF2

FKBP12 in complex with the BMP potentiator compound 6 at 1.03A resolution

6YF2 の概要

• エントリーDOI: 10.2210/pdb6yf2/pdb
• 関連するPDBエントリー: 6YF0 6YF1
• 分子名称: Peptidyl-prolyl cis-trans isomerase FKBP1A, (1~{R},9~{S},12~{S},13~{R},14~{S},17~{R},18~{E},21~{S},23~{S},24~{R},25~{S},27~{R})-23,25-dimethoxy-12-[(~{E})-1-[(1~{R},3~{R},4~{R})-3-methoxy-4-oxidanyl-cyclohexyl]prop-1-en-2-yl]-13,19,21,27-tetramethyl-1,14-bis(oxidanyl)-17-(2-oxidanylidenepropyl)-11,28-dioxa-4-azatricyclo[22.3.1.0^{4,9}]octacos-18-ene-2,3,10,16-tetrone, CADMIUM ION, ... (6 entities in total)
• 機能のキーワード: immunosuppression, immunosuppressant, bmp enhancer program, isomerase
• 由来する生物種: Homo sapiens (Human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 13017.00

構造登録者

Kallen, J. (登録日: 2020-03-25, 公開日: 2021-03-10, 最終更新日: 2024-01-24)

主引用文献

Larraufie, M.H.,Gao, X.,Xia, X.,Devine, P.J.,Kallen, J.,Liu, D.,Michaud, G.,Harsch, A.,Savage, N.,Ding, J.,Tan, K.,Mihalic, M.,Roggo, S.,Canham, S.M.,Bushell, S.M.,Krastel, P.,Gao, J.,Izaac, A.,Altinoglu, E.,Lustenberger, P.,Salcius, M.,Harbinski, F.,Williams, E.T.,Zeng, L.,Loureiro, J.,Cong, F.,Fryer, C.J.,Klickstein, L.,Tallarico, J.A.,Jain, R.K.,Rothman, D.M.,Wang, S.
Phenotypic screen identifies calcineurin-sparing FK506 analogs as BMP potentiators for treatment of acute kidney injury.
Cell Chem Biol, 28:1271-, 2021

PubMed Abstract: 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.

PubMed: 33894161
DOI: 10.1016/j.chembiol.2021.04.001

実験手法

X-RAY DIFFRACTION (1.03 Å)