title: In vitro evolution of an HIV integrase binding protein from a library of C-terminal domain γS-crystallin variants.
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.
authors.affiliation: Department of Molecular Biology & Biochemistry, University of California Irvine, Irvine, CA 92697-3900, USA.
authors.forename: Issa S
authors.initials: IS
authors.lastname: Moody
authors.forename: Shawn C
authors.initials: SC
authors.lastname: Verde
authors.forename: Cathie M
authors.initials: CM
authors.lastname: Overstreet
authors.forename: W
authors.initials: W
authors.lastname: Edward Robinson
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D008958:Models, Molecular; D019151:Peptide Library; D011485:Protein Binding; D015202:Protein Engineering / Q000379:methods*; D017434:Protein Structure, Tertiary; D038222:gamma-Crystallins / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*
chemical_list: D019428:HIV Integrase Inhibitors; D019151:Peptide Library; D038222:gamma-Crystallins; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1