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Article

Molecular Targeting of Inhibitor of Apoptosis Proteins Based on Small Molecule Mimics of Natural Binding Partners^†

Rachael A. Kipp,^‡ Martin A. Case,^‡ Aislyn D. Wist,^‡ Catherine M. Cresson,^‡ Maria Carrell,^‡ Erin Griner,^‡ Arun Wiita,^‡ Philip A. Albiniak,^‡ Jijie Chai,^§ Yigong Shi,^§ Martin F. Semmelhack,^‡ and George L. McLendon*^‡

Department of Chemistry, Frick Laboratory, and Department of Molecular Biology, Lewis Thomas Laboratory, Princeton University, Washington Road, Princeton, New Jersey 08544

Biochemistry, 2002, 41 (23), pp 7344–7349

DOI: 10.1021/bi0121454

Publication Date (Web): May 17, 2002

†

This work was supported by the National Institutes of Health under Grants GM59348-02 and F32 GM20804.

‡

Department of Chemistry, Frick Laboratory.

Department of Molecular Biology, Lewis Thomas Laboratory.

To whom correspondence should be addressed. Telephone: (609) 258-6808. Fax: (609) 258-6746. E-mail: glm@princeton.edu.

Abstract

An assay based on a solvent-sensitive fluorogenic dye molecule, badan, is used to test the binding affinity of a library of tetrapeptide molecules for the BIR3 (baculovirus IAP repeat) domain of XIAP (X-linked inhibitor of apoptosis protein). The fluorophore is attached to a tetrapeptide, Ala-Val-Pro-Cys-NH₂, through a thiol linkage and, upon binding to XIAP, undergoes a solvatochromic shift in fluorescence emission. When a molecule (e.g., a natural protein known to bind to XIAP or a tetrapeptide mimic) displaces the dye, the emission shifts back to the spectrum observed in water. As emission intensity is related to the binding of the tetrapeptide, the intensity can be used to determine the equilibrium constant, K, for the displacement of the dye by the tetrapeptide. The results permit residue-specific analysis of the interaction. Furthermore, we show that hydrophobic effects in the fourth position are general and can effectively increase overall affinity.

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Published In Issue June 11, 2002
Received December 11, 2001
Revised Manuscript Received March 28, 2002

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Article

Molecular Targeting of Inhibitor of Apoptosis Proteins Based on Small Molecule Mimics of Natural Binding Partners^†