6ne4
Designed repeat protein specifically in complex with Fz7CRD
Structural highlights
FunctionFZD7_HUMAN Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Publication Abstract from PubMedTo discriminate between closely related members of a protein family that differ at a limited number of spatially distant positions is a challenge for drug discovery. We describe a combined computational design and experimental selection approach for generating binders targeting functional sites with large, shape complementary interfaces to read out subtle sequence differences for subtype-specific antagonism. Repeat proteins are computationally docked against a functionally relevant region of the target protein surface that varies in the different subtypes, and the interface sequences are optimized for affinity and specificity first computationally and then experimentally. We used this approach to generate a series of human Frizzled (Fz) subtype-selective antagonists with extensive shape complementary interaction surfaces considerably larger than those of repeat proteins selected from random libraries. In vivo administration revealed that Wnt-dependent pericentral liver gene expression involves multiple Fz subtypes, while maintenance of the intestinal crypt stem cell compartment involves only a limited subset. Receptor subtype discrimination using extensive shape complementary designed interfaces.,Dang LT, Miao Y, Ha A, Yuki K, Park K, Janda CY, Jude KM, Mohan K, Ha N, Vallon M, Yuan J, Vilches-Moure JG, Kuo CJ, Garcia KC, Baker D Nat Struct Mol Biol. 2019 May 13. pii: 10.1038/s41594-019-0224-z. doi:, 10.1038/s41594-019-0224-z. PMID:31086346[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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