6OQA

Crystal structure of CEP250 bound to FKBP12 in the presence of FK506-like novel natural product

Summary for 6OQA

• Entry DOI: 10.2210/pdb6oqa/pdb
• Descriptor: Peptidyl-prolyl cis-trans isomerase FKBP1A, MALONIC ACID, Centrosome-associated protein CEP250, ... (11 entities in total)
• Functional Keywords: fkbp12, cep250, natural product, ternary complex, cell cycle, isomerase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 8
• Total formula weight: 100330.44

Authors

Lee, S.-J.,Shigdel, U.K.,Townson, S.A.,Verdine, G.L. (deposition date: 2019-04-26, release date: 2020-04-29, Last modification date: 2024-03-13)

Primary citation

Shigdel, U.K.,Lee, S.J.,Sowa, M.E.,Bowman, B.R.,Robison, K.,Zhou, M.,Pua, K.H.,Stiles, D.T.,Blodgett, J.A.V.,Udwary, D.W.,Rajczewski, A.T.,Mann, A.S.,Mostafavi, S.,Hardy, T.,Arya, S.,Weng, Z.,Stewart, M.,Kenyon, K.,Morgenstern, J.P.,Pan, E.,Gray, D.C.,Pollock, R.M.,Fry, A.M.,Klausner, R.D.,Townson, S.A.,Verdine, G.L.
Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface.
Proc.Natl.Acad.Sci.USA, 117:17195-17203, 2020

PubMed Abstract: The 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.

PubMed: 32606248
DOI: 10.1073/pnas.2006560117

Experimental method

X-RAY DIFFRACTION (2.2 Å)