Photon Factory Activity Report 2005 #23 Part B (2006)
ChemistryNW2/2005G153

Sequence-Selective Recognition of Peptides within the Single Binding Pocket of a
Self-Assembled Coordination Cage
Shohei Tashiro,1 Masahide Tominaga,1 Masaki Kawano,1 Bruno Therrien,1 Tomoji Ozeki,2 and1Makoto Fujita *1
Department of Applied Chemistry, The University of Tokyo, CREST, Japan Science andTechnology Corporation (JST), Bunkyo-ku, Tokyo 113-8656, Japan2
Department of Chemistry and Materials Science, Tokyo Institute of Technology, Meguro-ku,Tokyo 152-8551, Japan
Introduction
Sequence-selective recognition of peptides is expectedto be an essential process for the site-specific recognitionof protein surfaces, which leads to the control of proteinfunctions and to the understanding of biological events at
protein surfaces such as protein-protein or proteinoligopeptide interactions. Although a few groups havereported artificial receptors for sequence-selective peptide
recognition, the highly designed receptors are in theirearly stages. Here, we report that the single binding
pocket of self-assembled coordination cage 1 canaccommodate oligopeptides in a highly sequenceselective fashion. Having a large hydrophobic cavity,
cage 1 binds as many as three amino acid residues. X-ray
analyses reveal that the sequence-selective recognition is
ascribed to cooperative multiple interactions between the1residues and the cavity.

Results
We found that cage 1 bound Ac-Trp-Trp-Ala-NH2 (2)
6–1
very strongly (Ka >10 M ). Strong binding was specificto the Trp-Trp-Ala sequence because the binding oftripeptides possessing those same residues in different
sequences, such as Ac-Trp-Ala-Trp-NH2 (3) and Ac-Ala5
Trp-Trp-NH2 (4), was much less effective (Ka = 2.5 x 104–1
and 2.1 x 10 M , respectively). Even singly mutatedtripeptides, such as Ac-Trp-Trp-Gly-NH2 (5) and Ac-Trp4
Tyr-Ala-NH2 (6), showed poorer affinity (Ka = 7.4 x 104–1
and 5.3 x 10 M , respectively) although they have very
similar aromatic-aromatic-aliphatic sequences. These
results suggest that the two indole rings and the Ala

32

Users' Report

Figure1. Crystal structure of 1•2. Peptide 2 in thecavity is represented by (a) space-filling and (b)cylindrical model. The π−π interactions of 1 withindole rings of (c) W1 and (d) W2. (e) The CH-πinteraction between 1 and methyl group of A3.
methyl group in 2 should cooperatively interact with thecage in the 1•2 complex.
In fact, the multiple interactions of the methyl andindole groups with the cage were revealed by X-ray
crystallographic analysis. Single crystals were obtained
after an aqueous solution of 1•2 complex stood at room
temperature for 4 d. The diffraction data were collectedby synchrotron X-ray irradiation. The crystallographic
analysis showed that tripeptide 2 is fully encapsulated in
the cavity of 1 (Figure 1a,b). As predicted, all residues
interact very efficiently with cage 1. Namely, two indole
rings are stacked on the triazine ligand by π−π interaction(3.4-3.5 Å), while the Ala methyl group interacts withanother ligand by CH-π contact (2.5 Å) (Figure 1c-e).
Despite the enclathration within the restricted cavity, thepeptide backbone is fixed in an extended conformation.
References[1] S. Tashiro et. al. J. Am. Chem. Soc., 127, 4546 (2005).
*mfujita@appchem.t.u-tokyo.ac.jp