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Artificial protein cavities as specific ligand-binding templates: characterization of an engineered heterocyclic cation-binding site that preserves the evolved specificity of the parent protein.

Musah RA, Jensen GM, Bunte SW, Rosenfeld RJ, Goodin DB
J Mol Biol 315 845-57 (2002)
Related entries: 1aeb, 1aed, 1aee, 1aef, 1aeg, 1aeh, 1aej, 1aem, 1aen, 1aeo, 1aeq, 1cca, 1ccb, 1ccc, 1cmp, 1cmq

Cited: 32 times
EuropePMC logo PMID: 11812152

Abstract

Cavity complementation has been observed in many proteins, where an appropriate small molecule binds to a cavity-forming mutant. Here, the binding of compounds to the W191G cavity mutant of cytochrome c peroxidase is characterized by X-ray crystallography and binding thermodynamics. Unlike cavities created by removal of hydrophobic side-chains, the W191G cavity does not bind neutral or hydrophobic compounds, but displays a strong specificity for heterocyclic cations, consistent with the role of the protein to stabilize a tryptophan radical at this site. Ligand dissociation constants for the protonated cationic state ranged from 6 microM for 2-amino-5-methylthiazole to 1 mM for neutral ligands, and binding was associated with a large enthalpy-entropy compensation. X-ray structures show that each of 18 compounds with binding behavior bind specifically within the artificial cavity and not elsewhere in the protein. The compounds make multiple hydrogen bonds to the cavity walls using a subset of the interactions seen between the protein and solvent in the absence of ligand. For all ligands, every atom that is capable of making a hydrogen bond does so with either protein or solvent. The most often seen interaction is to Asp235, and most compounds bind with a specific orientation that is defined by their ability to interact with this residue. Four of the ligands do not have conventional hydrogen bonding atoms, but were nevertheless observed to orient their most polar CH bond towards Asp235. Two of the larger ligands induce disorder in a surface loop between Pro190 and Asn195 that has been identified as a mobile gate to cavity access. Despite the predominance of hydrogen bonding and electrostatic interactions, the small variation in observed binding free energies were not correlated readily with the strength, type or number of hydrogen bonds or with calculated electrostatic energies alone. Thus, as with naturally occurring binding sites, affinities to W191G are likely to be due to a subtle balance of polar, non-polar, and solvation terms. These studies demonstrate how cavity complementation and judicious choice of site can be used to produce a protein template with an unusual ligand-binding specificity.

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  23. Modeling regionalized volumetric differences in protein-ligand binding cavities. Chen BY, Bandyopadhyay S. Proteome Sci 10 Suppl 1 S6 (2012)
  24. Exploring Protein Cavities through Rigidity Analysis. Mason S, Chen BY, Jagodzinski F. Molecules 23 E351 (2018)
  25. Trapping of peptide-based surrogates in an artificially created channel of cytochrome c peroxidase. Hays AM, Gray HB, Goodin DB. Protein Sci 12 278-287 (2003)
  26. Impact of Proximal and Distal Pocket Site-Directed Mutations on the Ferric/Ferrous Heme Redox Potential of Yeast Cytochrome-c-Peroxidase. Jensen GM, Goodin DB. Theor Chem Acc 130 1185-1196 (2011)
  27. LifeSoaks: a tool for analyzing solvent channels in protein crystals and obstacles for soaking experiments. Pletzer-Zelgert J, Ehrt C, Fender I, Griewel A, Flachsenberg F, Klebe G, Rarey M. Acta Crystallogr D Struct Biol 79 837-856 (2023)
  28. Why Do Most Aromatics Fail to Support Hole Hopping in the Cytochrome c Peroxidase-Cytochrome c Complex? Ru X, Crane BR, Zhang P, Beratan DN. J Phys Chem B 125 7763-7773 (2021)


Related citations provided by authors (2)

  1. Small molecule binding to an artificially created cavity at the active site of cytochrome c peroxidase.. Fitzgerald MM, Churchill MJ, McRee DE, Goodin DB Biochemistry 33 3807-18 (1994)
  2. The Asp-His-Fe triad of cytochrome c peroxidase controls the reduction potential, electronic structure, and coupling of the tryptophan free radical to the heme.. Goodin DB, McRee DE Biochemistry 32 3313-24 (1993)

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