6TCH

Binary complex of 14-3-3 sigma and a high-affinity non-canonical 9-mer peptide binder

Summary for 6TCH

• Entry DOI: 10.2210/pdb6tch/pdb
• Descriptor: 14-3-3 protein sigma, DLY-NVA-PPN-KCJ-SEP-PPN-B3S-BAL-PPN-LYS, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: non-canonical peptide, 14-3-3 protein sigma, protein-peptide interaction, phosphopeptide, non-natural amino acids, protein binding, peptide binding protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 28116.05

Authors

Somsen, B.A.,Ottmann, C. (deposition date: 2019-11-06, release date: 2020-07-01, Last modification date: 2024-01-24)

Primary citation

Quartararo, A.J.,Gates, Z.P.,Somsen, B.A.,Hartrampf, N.,Ye, X.,Shimada, A.,Kajihara, Y.,Ottmann, C.,Pentelute, B.L.
Ultra-large chemical libraries for the discovery of high-affinity peptide binders.
Nat Commun, 11:3183-3183, 2020

PubMed Abstract: High-diversity genetically-encoded combinatorial libraries (10-10 members) are a rich source of peptide-based binding molecules, identified by affinity selection. Synthetic libraries can access broader chemical space, but typically examine only ~ 10 compounds by screening. Here we show that in-solution affinity selection can be interfaced with nano-liquid chromatography-tandem mass spectrometry peptide sequencing to identify binders from fully randomized synthetic libraries of 10 members-a 100-fold gain in diversity over standard practice. To validate this approach, we show that binders to a monoclonal antibody are identified in proportion to library diversity, as diversity is increased from 10-10. These results are then applied to the discovery of p53-like binders to MDM2, and to a family of 3-19 nM-affinity, α/β-peptide-based binders to 14-3-3. An X-ray structure of one of these binders in complex with 14-3-3σ is determined, illustrating the role of β-amino acids in facilitating a key binding contact.

PubMed: 32576815
DOI: 10.1038/s41467-020-16920-3

Experimental method

X-RAY DIFFRACTION (1.801 Å)