Discovery of phosphotyrosine-binding oligopeptides with supramolecular target selectivity.

Autor: Pina AS; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt.; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Morgado L; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Duncan KL; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt.; Department of Pure & Applied Chemistry, University of Strathclyde 295 Cathedral Street Glasgow G1 1XL UK., Carvalho S; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Carvalho HF; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Barbosa AJM; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., de P Mariz B; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Moreira IP; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Kalafatovic D; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt., Morais Faustino BM; CENIMAT/I3N, Department of Materials Science, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Narang V; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt., Wang T; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt.; Imaging Facility of CUNY ASRC 85 St Nicholas Terrace New York 10031 USA., Pappas CG; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt.; Department of Pure & Applied Chemistry, University of Strathclyde 295 Cathedral Street Glasgow G1 1XL UK., Ferreira I; CENIMAT/I3N, Department of Materials Science, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Roque ACA; Associate Laboratory i4HB - Institute for Health and Bioeconomy, NOVA School of Science and Technology, NOVA University Lisbon 2829-516 Caparica Portugal cecilia.roque@fct.unl.pt.; UCIBIO - Applied Molecular Biosciences Unit, Department of Chemistry, School of Science and Technology, NOVA University of Lisbon 2829-516 Caparica Portugal., Ulijn RV; Advanced Science Research Center (ASRC) at the Graduate Center, City University of New York (CUNY) NY 10031 USA ana.pina@fct.unl.pt.; Hunter College of CUNY, Department of Chemistry and Biochemistry 695 Park Avenue New York 10065 USA.; PhD Programs in Chemistry and Biochemistry, The Graduate Center of CUNY New York 10016 USA rulijn@gc.cuny.edu.
Jazyk: angličtina
Zdroj: Chemical science [Chem Sci] 2021 Dec 07; Vol. 13 (1), pp. 210-217. Date of Electronic Publication: 2021 Dec 07 (Print Publication: 2021).
DOI: 10.1039/d1sc04420f
Abstrakt: We demonstrate phage-display screening on self-assembled ligands that enables the identification of oligopeptides that selectively bind dynamic supramolecular targets over their unassembled counterparts. The concept is demonstrated through panning of a phage-display oligopeptide library against supramolecular tyrosine-phosphate ligands using 9-fluorenylmethoxycarbonyl-phenylalanine-tyrosine-phosphate (Fmoc-F p Y) micellar aggregates as targets. The 14 selected peptides showed no sequence consensus but were enriched in cationic and proline residues. The lead peptide, KVYFSIPWRVPM-NH 2 (P7) was found to bind to the Fmoc-F p Y ligand exclusively in its self-assembled state with K D = 74 ± 3 μM. Circular dichroism, NMR and molecular dynamics simulations revealed that the peptide interacts with Fmoc-F p Y through the KVYF terminus and this binding event disrupts the assembled structure. In absence of the target micellar aggregate, P7 was further found to dynamically alternate between multiple conformations, with a preferred hairpin-like conformation that was shown to contribute to supramolecular ligand binding. Three identified phages presented appreciable binding, and two showed to catalyze the hydrolysis of a model para -nitro phenol phosphate substrate, with P7 demonstrating conformation-dependent activity with a modest k cat / K M = 4 ± 0.3 × 10 -4 M -1 s -1 .
Competing Interests: There are no conflicts to declare.
(This journal is © The Royal Society of Chemistry.)
Databáze: MEDLINE
Externí odkaz: