6PIT

Estrogen Receptor Alpha Ligand Binding Domain Y537S Mutant in Complex with SRC2 Stapled Peptide 41A and Estradiol

Summary for 6PIT

• Entry DOI: 10.2210/pdb6pit/pdb
• Descriptor: Estrogen receptor, Stapled Peptide 41A, ESTRADIOL, ... (5 entities in total)
• Functional Keywords: hormone, nuclear receptor, estrogen, stapled peptide, transcription
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 63616.96

Authors

Fanning, S.W.,Montgomery, J.E.,Greene, G.L.,Moellering, R.E. (deposition date: 2019-06-27, release date: 2019-10-16, Last modification date: 2023-11-15)

Primary citation

Montgomery, J.E.,Donnelly, J.A.,Fanning, S.W.,Speltz, T.E.,Shangguan, X.,Coukos, J.S.,Greene, G.L.,Moellering, R.E.
Versatile Peptide Macrocyclization with Diels-Alder Cycloadditions.
J.Am.Chem.Soc., 141:16374-16381, 2019

PubMed Abstract: Macrocyclization can improve bioactive peptide ligands through preorganization of molecular topology, leading to improvement of pharmacologic properties like binding affinity, cell permeability, and metabolic stability. Here we demonstrate that Diels-Alder [4 + 2] cycloadditions can be harnessed for peptide macrocyclization and stabilization within a range of peptide scaffolds and chemical environments. Diels-Alder cyclization of diverse diene-dienophile reactive pairs proceeds rapidly, in high yield and with tunable stereochemical preferences on solid-phase or in aqueous solution. This reaction can be applied alone or in concert with other stabilization chemistries, such as ring-closing olefin metathesis, to stabilize loop, turn, and α-helical secondary structural motifs. NMR and molecular dynamics studies of model loop peptides confirmed preferential formation of cycloadduct stereochemistry, imparting significant structural rigidity to the peptide backbone that resulted in augmented protease resistance and increased biological activity of a Diels-Alder cyclized (DAC) RGD peptide. Separately, we demonstrated the stabilization of DAC α-helical peptides derived from the ERα-binding protein SRC2. We solved a 2.25 Å cocrystal structure of one DAC helical peptide bound to ERα, which unequivocally corroborated stereochemistry of the resulting Diels-Alder adduct, and confirmed that the unique architecture of stabilizing motifs formed with this chemistry can directly contribute to target binding. These data establish Diels-Alder cyclization as a versatile approach to stabilize diverse protein structural motifs under a range of chemical environments.

PubMed: 31523967
DOI: 10.1021/jacs.9b07578

Experimental method

X-RAY DIFFRACTION (2.25 Å)