6oqa
From Proteopedia
Crystal structure of CEP250 bound to FKBP12 in the presence of FK506-like novel natural product
Structural highlights
Disease[CP250_HUMAN] The disease is caused by mutations affecting the gene represented in this entry. 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] [CP250_HUMAN] May be involved in ciliogenesis (PubMed:28005958). Probably plays an important role in centrosome cohesion during interphase.[3] Publication Abstract from PubMedThe vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12. Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.,Shigdel UK, Lee SJ, Sowa ME, Bowman BR, Robison K, Zhou M, Pua KH, Stiles DT, Blodgett JAV, Udwary DW, Rajczewski AT, Mann AS, Mostafavi S, Hardy T, Arya S, Weng Z, Stewart M, Kenyon K, Morgenstern JP, Pan E, Gray DC, Pollock RM, Fry AM, Klausner RD, Townson SA, Verdine GL Proc Natl Acad Sci U S A. 2020 Jul 21;117(29):17195-17203. doi:, 10.1073/pnas.2006560117. Epub 2020 Jun 30. PMID:32606248[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||||||
