A substrate selected by phage display exhibits enhanced side-chain hydrogen bonding to HIV-1 protease

Acta Crystallogr D Struct Biol. 2018 Jul 1;74(Pt 7):690-694. doi: 10.1107/S2059798318006691. Epub 2018 Jun 27.


Crystal structures of inactive variants of HIV-1 protease bound to peptides have revealed how the enzyme recognizes its endogenous substrates. The best of the known substrates is, however, a nonnatural substrate that was identified by directed evolution. The crystal structure of the complex between this substrate and the D25N variant of the protease is reported at a resolution of 1.1 Å. The structure has several unprecedented features, especially the formation of additional hydrogen bonds between the enzyme and the substrate. This work expands the understanding of molecular recognition by HIV-1 protease and informs the design of new substrates and inhibitors.

Keywords: HIV-1 protease; hydrogen bonds; molecular recognition; phage display.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Directed Molecular Evolution
  • Genetic Variation / genetics
  • HIV Protease / chemistry*
  • Humans
  • Hydrogen Bonding
  • Peptide Library*
  • Peptides / chemistry
  • Protein Binding
  • Substrate Specificity


  • Peptide Library
  • Peptides
  • HIV Protease
  • p16 protease, Human immunodeficiency virus 1