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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 26 407-414 (2019)
Related entries: 6ne1, 6ne2, 6ne4

Cited: 18 times
EuropePMC logo PMID: 31086346

Abstract

To 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.

Articles - 6ndz mentioned but not cited (3)

  1. Next-Generation Surrogate Wnts Support Organoid Growth and Deconvolute Frizzled Pleiotropy In Vivo. Miao Y, Ha A, de Lau W, Yuki K, Santos AJM, You C, Geurts MH, Puschhof J, Pleguezuelos-Manzano C, Peng WC, Senlice R, Piani C, Buikema JW, Gbenedio OM, Vallon M, Yuan J, de Haan S, Hemrika W, Rösch K, Dang LT, Baker D, Ott M, Depeille P, Wu SM, Drost J, Nusse R, Roose JP, Piehler J, Boj SF, Janda CY, Clevers H, Kuo CJ, Garcia KC. Cell Stem Cell 27 840-851.e6 (2020)
  2. 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 26 407-414 (2019)
  3. Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8. Zhao Y, Ren J, Hillier J, Lu W, Jones EY. J Med Chem 63 3252-3260 (2020)


Reviews citing this publication (3)

  1. Protein Assembly by Design. Zhu J, Avakyan N, Kakkis A, Hoffnagle AM, Han K, Li Y, Zhang Z, Choi TS, Na Y, Yu CJ, Tezcan FA. Chem Rev 121 13701-13796 (2021)
  2. LRPs in WNT Signalling. Davidson G. Handb Exp Pharmacol 269 45-73 (2021)
  3. The structural biology of canonical Wnt signalling. Agostino M, Pohl SÖ. Biochem Soc Trans 48 1765-1780 (2020)

Articles citing this publication (12)

  1. Engineered ACE2 receptor traps potently neutralize SARS-CoV-2. Glasgow A, Glasgow J, Limonta D, Solomon P, Lui I, Zhang Y, Nix MA, Rettko NJ, Zha S, Yamin R, Kao K, Rosenberg OS, Ravetch JV, Wiita AP, Leung KK, Lim SA, Zhou XX, Hobman TC, Kortemme T, Wells JA. Proc Natl Acad Sci U S A 117 28046-28055 (2020)
  2. Structure of human Frizzled5 by fiducial-assisted cryo-EM supports a heterodimeric mechanism of canonical Wnt signaling. Tsutsumi N, Mukherjee S, Waghray D, Janda CY, Jude KM, Miao Y, Burg JS, Aduri NG, Kossiakoff AA, Gati C, Garcia KC. Elife 9 e58464 (2020)
  3. Tertiary motifs as building blocks for the design of protein-binding peptides. Swanson S, Sivaraman V, Grigoryan G, Keating AE. Protein Sci 31 e4322 (2022)
  4. Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells. Gumber D, Do M, Suresh Kumar N, Sonavane PR, Wu CCN, Cruz LS, Grainger S, Carson D, Gaasterland T, Willert K. Elife 9 e63060 (2020)
  5. De novo design of protein interactions with learned surface fingerprints. Gainza P, Wehrle S, Van Hall-Beauvais A, Marchand A, Scheck A, Harteveld Z, Buckley S, Ni D, Tan S, Sverrisson F, Goverde C, Turelli P, Raclot C, Teslenko A, Pacesa M, Rosset S, Georgeon S, Marsden J, Petruzzella A, Liu K, Xu Z, Chai Y, Han P, Gao GF, Oricchio E, Fierz B, Trono D, Stahlberg H, Bronstein M, Correia BE. Nature 617 176-184 (2023)
  6. Robust Colonic Epithelial Regeneration and Amelioration of Colitis via FZD-Specific Activation of Wnt Signaling. Xie L, Fletcher RB, Bhatia D, Shah D, Phipps J, Deshmukh S, Zhang H, Ye J, Lee S, Le L, Newman M, Chen H, Sura A, Gupta S, Sanman LE, Yang F, Meng W, Baribault H, Vanhove GF, Yeh WC, Li Y, Lu C. Cell Mol Gastroenterol Hepatol 14 435-464 (2022)
  7. Isoform-specific inhibition of FGFR signaling achieved by a de-novo-designed mini-protein. Park JS, Choi J, Cao L, Mohanty J, Suzuki Y, Park A, Baker D, Schlessinger J, Lee S. Cell Rep 41 111545 (2022)
  8. Substrate Specificity and Structural Modeling of Human Carboxypeptidase Z: A Unique Protease with a Frizzled-Like Domain. Garcia-Pardo J, Tanco S, Garcia-Guerrero MC, Dasgupta S, Avilés FX, Lorenzo J, Fricker LD. Int J Mol Sci 21 E8687 (2020)
  9. Therapeutic blood-brain barrier modulation and stroke treatment by a bioengineered FZD4-selective WNT surrogate in mice. Ding J, Lee SJ, Vlahos L, Yuki K, Rada CC, van Unen V, Vuppalapaty M, Chen H, Sura A, McCormick AK, Tomaske M, Alwahabi S, Nguyen H, Nowatzke W, Kim L, Kelly L, Vollrath D, Califano A, Yeh WC, Li Y, Kuo CJ. Nat Commun 14 2947 (2023)
  10. Controlling Wnt Signaling Specificity and Implications for Targeting WNTs Pharmacologically. Sonavane PR, Willert K. Handb Exp Pharmacol 269 3-28 (2021)
  11. Exploring binding positions and backbone conformations of peptide ligands of proteins with a backbone-centred statistical energy function. Zhang L, Liu H. J Comput Aided Mol Des 37 463-478 (2023)
  12. Receptor Elimination by E3 Ubiquitin Ligase Recruitment (REULR): A Targeted Protein Degradation Toolbox. Siepe DH, Picton LK, Garcia KC. ACS Synth Biol 12 1081-1093 (2023)


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