6YF2
FKBP12 in complex with the BMP potentiator compound 6 at 1.03A resolution
Summary for 6YF2
| Entry DOI | 10.2210/pdb6yf2/pdb |
| Related | 6YF0 6YF1 |
| Descriptor | 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) |
| Functional Keywords | immunosuppression, immunosuppressant, bmp enhancer program, isomerase |
| Biological source | Homo sapiens (Human) |
| Total number of polymer chains | 1 |
| Total formula weight | 13017.00 |
| Authors | Kallen, J. (deposition date: 2020-03-25, release date: 2021-03-10, Last modification date: 2024-01-24) |
| Primary citation | 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 Cited by 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: 33894161DOI: 10.1016/j.chembiol.2021.04.001 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.03 Å) |
Structure validation
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