About: Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

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About: Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface Goto Sponge NotDistinct Permalink

An Entity of Type : schema:ScholarlyArticle, within Data Space : covidontheweb.inria.fr associated with source document(s)

Attributes	Values
type	Academic Article research paper schema:ScholarlyArticle
isDefinedBy	Covid-on-the-Web dataset
has title	Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface
Creator	Pollock, Roy Klausner, Richard Arya, Sukrat Blodgett, Joshua Bowman, Brian Fry, Andrew Gray, Daniel Hardy, Tara Kenyon, Kyle Lee, Seung-Joo Mann, Alan Morgenstern, Jay Mostafavi, Siavash Pan, Ende Rajczewski, Andrew Robison, Keith Shigdel, Uddhav Sowa, Mathew Stewart, Michelle Stiles, Dylan Udwary, Daniel Weng, Zhigang Zhou, Minyun Khian, Hong Pua,
Source	Medline; PMC
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.
has issue date	2020-07-21(xsd:dateTime)
bibo:doi	10.1073/pnas.2006560117
bibo:pmid	32606248
has license	cc-by
sha1sum (hex)	ecc5667aae6f57f572d884f79ffaf24ba7a92022
schema:url	https://doi.org/10.1073/pnas.2006560117
resource representing a document's title	Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface
has PubMed Central identifier	PMC7382241
has PubMed identifier	32606248
schema:publication	Proc Natl Acad Sci U S A
resource representing a document's body	covid:ecc5667aae6f57f572d884f79ffaf24ba7a92022#body_text
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