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Bioorg Med Chem Lett. 2012 Sep 1;22(17):5584-9. doi: 10.1016/j.bmcl.2012.07.008. Epub 2012 Jul 10.

In vitro evolution of an HIV integrase binding protein from a library of C-terminal domain γS-crystallin variants.

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1
Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697-3900, USA.

Abstract

A protein without natural binding functions was engineered to bind HIV-1 integrase. Phage display selections applied a library of variants based on the C-terminal domain of the eye lens protein human γS-crystallin. Multiple loop regions were altered to encode libraries with ≈3.6 × 10(11) different variants. A crystallin variant, termed integrase binding protein-10 (IBP-10), inhibits integrase catalysis with nanomolar K(i) values. IBP-10 interacts with the integrase C-terminal domain and inhibits integrase substrate affinity. This allosteric mechanism allows IBP-10 to inhibit drug-resistant integrase variants. The results demonstrate the applicability of the crystallin scaffold for the discovery of binding partners and enzyme inhibitors.

PMID:
22858140
PMCID:
PMC3956296
DOI:
10.1016/j.bmcl.2012.07.008
[Indexed for MEDLINE]
Free PMC Article
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