SRC2-3 binds to vitamin D receptor with high sensitivity and strong affinity

Structural Basis for α‐Helix Mimicry and Inhibition of Protein–Protein Interactions with Oligourea Foldamers

“…The structure between VDR and 11 reveals that the lysine side chain K u 7 in 11 provides an additional polar interaction by forming a salt bridge with E285, an interaction which is not present in the structure of SRC1‐2 bound to VDR due to the shorter side chain of H6. Notably, a similar salt bridge interaction is formed between R6 and D253 in the structure of SRC2‐3 bound to rat VDR [14] . Taken together these results parallel the observations made with the 4 ‐MDM2 structure and underline the importance of tuning the side chain substitution pattern ( β C vs. α C) for effective α‐helix mimicry.…”

“…The crystal structures of liganded VDR LBD in complex with coregulatory peptides SRC1‐2 (PDB ID: 2HC4, [13] 4G1Z [22] ) and SRC2‐3 (PDB ID: 5H1E [14] ) provided a structural basis for the rational design of chimeric foldamers (≈8–11 residue long). SRC1‐2 and SRC2‐3 are tridecapeptides that comprise a central consensus LXXLL motif and differ by their flanking residues.…”

“…This is explained in part by the additional hydrophobic contact at the surface of the VDR [23] . Additional polar contact may also contribute to the stronger affinity of SRC2‐3 for VDR [14] …”

“…Thecrystal structures of liganded VDR LBD in complex with coregulatory peptides SRC1-2 (PDB ID:2 HC4, [13] 4G1Z [22] )a nd SRC2-3 (PDB ID:5 H1E [14] )p rovided as tructural basis for the rational design of chimeric foldamers ( % 8-11 residue long). SRC1-2 and SRC2-3 are tridecapeptides that comprise ac entral consensus LXXLL motif and differ by their flanking residues.Both sequences contain ahydrophobic residue (L/I) N-terminal to the LXXLL motif and bind VDR with relatively high affinity compared to other coactivators such as SRC1-1 and SRC2-1 which contain apolar residue at that position.…”

“…C) Peptides PMI, SRC1‐2, and SRC2‐3 used as starting points to design corresponding peptide–oligourea ligands. Bound conformation to their respective targets, namely MDM2 (PDB ID: 3EQS [12] ) and VDR (PDB ID: 2HC4 [13] and 5H1E [14] ).…”