Structural characterization of a β-turn mimic within a protein–protein interface

Abstract

β-turns are secondary structure elements not only exposed on protein surfaces, but also frequently found to be buried in protein–protein interfaces. Protein engineering so far considered mainly the backbone-constraining properties of synthetic β-turn mimics as parts of surface-exposed loops. A β-turn mimic, Hot═Tap, that is available in gram amounts, provides two hydroxyl groups that enhance its turn-inducing properties besides being able to form side-chain-like interactions. NMR studies on cyclic hexapeptides harboring the Hot═Tap dipeptide proved its strong β-turn-inducing capability. Crystallographic analyses of the trimeric fibritin-foldon/Hot═Tap hybrid reveal at atomic resolution how Hot═Tap replaces a βI’-turn by a βII’-type structure. Furthermore, Hot═Tap adapts to the complex protein environment by participating in several direct and water-bridged interactions across the foldon trimer interface. As building blocks, β-turn mimics capable of both backbone and side-chain mimicry may simplify the design of synthetic proteins.

Cadmium–cysteine coordination in the BK inner pore region and its structural and functional implications

“…In addition to breaks or kinks in α-helices, proline is also frequently found in β-turns (28), with two residues adjacent to proline close enough to allow Cd 2+ coordination. In such structures, proline is often followed by an acidic residue (29)(30)(31)(32). For example, the distance between I64-Cβ and E66-Cδ in a triplet sequence IPE found in a β-turn of the gene 3 protein structure is ∼6 Å, which is permissive for Cd 2+ coordination (29).…”

Filaggrin Peptides with β‐Hairpin Structure Bind Rheumatoid Arthritis Antibodies

“…With either the amino acids Ala (peptide 9) or d-Ala (peptide 10) at the position of Gly 11 , one b-turn structure is energetically favored, wherein d-Ala forms a bII'-turn. [18] While the d-Ala peptide has the same dispersion in the 1 H NMR spectrum as 4, the mutation to Ala at this position leads to a significantly lower dispersion. In contrast to the dAla mutant, the amide proton signal of Gly at the i + 2 position is strongly broadened in peptide 4.…”

“…[17] Numerous dipeptide mimetics are known for b-hairpins, forming a b-turn and inducing or stabilizing the hairpin fold, such as Hot = Tap, which even can mediate a protein-protein interaction. [18] In this work we describe the transfer of stabilizing interactions in a model hairpin structural motif to a biologically active filaggrin sequence. The conformationally uniform b-hairpin Bhp HV (2) published by Cochran et al was used as a model hairpin peptide.…”

Stabilization of a Natural β‐Hairpin by a Twist‐Compatible β‐Turn Mimetic

“…[14] Modifying the Foldon hairpin with the β-turn promoting Hot=Tap building block yields the trimeric [ΔGly . [3] It is remarkable that only minimal structural differences are detectable between the high-resolution X-ray structure of the [d-Ala 10 ,d-Phe 17 ] Foldon, the X-ray structure of fibritin (pdb-code 1OX3), the solution structure [15] and the recently deposited crystal structure (pdb-codes 1RFO; 4NCU) of the native Foldon and a covalently linked derivative (pdbcode 4NCW). [16] Both strands need to be in close spatial vicinity for the stabilization of a β-sheet, and this is accomplished by im-plementing clamps on one or both ends of the hairpin (Figure 2).…”

“…[3] The stepwise shortening of the peptide sequence of a folded domain (≈ 100 aa) below a critical length leads to the loss of structural properties of the remaining fragment. Chemical tools need to be developed that hold truncated stand-alone hairpin fragments (≈ 20 aa) in shape in order to assemble conformationally stable antibody epitopes or other protein interaction domains (Figure 1, lower row).…”