Cited by 426Enzyme Structure and FunctionProtein Structure and DynamicsCrystal structures of chemical compounds

Analysis of zinc binding sites in protein crystal structures

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Alberts, Ian L., Nadassy, Katalin, Wodak, Shoshana J.·1998·Protein Science

Abstract

The geometrical properties of zinc binding sites in a dataset of high quality protein crystal structures deposited in the Protein Data Bank have been examined to identify important differences between zinc sites that are directly involved in catalysis and those that play a structural role. Coordination angles in the zinc primary coordination sphere are compared with ideal values for each coordination geometry, and zinc coordination distances are compared with those in small zinc complexes from the Cambridge Structural Database as a guide of expected trends. We find that distances and angles in the primary coordination sphere are in general close to the expected (or ideal) values. Deviations occur primarily for oxygen coordinating atoms and are found to be mainly due to H‐bonding of the oxygen coordinating ligand to protein residues, bidentate binding arrangements, and multi‐zinc sites. We find that H‐bonding of oxygen containing residues (or water) to zinc bound histidines is almost universal in our dataset and defines the elec‐His‐Zn motif. Analysis of the stereochemistry shows that carboxyl elec‐His‐Zn motifs are geometrically rigid, while water elec‐His‐Zn motifs show the most geometrical variation. As catalytic motifs have a higher proportion of carboxyl elec atoms than structural motifs, they provide a more rigid framework for zinc binding. This is understood biologically, as a small distortion in the zinc position in an enzyme can have serious consequences on the enzymatic reaction. We also analyze the sequence pattern of the zinc ligands and residues that provide elecs, and identify conserved hydrophobic residues in the endopeptidases that also appear to contribute to stabilizing the catalytic zinc site. A zinc binding template in protein crystal structures is derived from these observations.

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  • An electrostatic model based on the filled valence orbital of Zn2+ cannot explain why histidine and cysteine are more common zinc-coordinating residues than the more electronegative carboxylates of glutamate and aspartate.

    “Also, an electrostatic model based on the filled valence orbital of the Zn2+ ion fails to explain the prevalence of histidine and cysteine over the more electronegative carboxylate groups of glutamate and aspartate as the most frequent zinc coordinating residues.14−17”

    From AutoDock4<sub>Zn</sub>: An Improved AutoDock Force Field for Small-Molecule Docking to Zinc Metalloproteins (2014) · cites this paper as [16]

    Section 2 (page unavailable) reports the frequency of zinc-coordinating residues in Figure 1, and the coordination-geometry discussion says histidine predominates in mono-zinc sites. Our copy does not establish the claimed overall comparison for both histidine and cysteine against glutamate and aspartate, or say that a filled-valence-orbital electrostatic model fails to explain it. (LLM, conf=0.76)

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Research works printed but not linked: 4

  1. [33]33. FA, Wilkinson G. 1988. Advanced inorgunic chemistry. New York: Wiley.
  2. [38]38. Eriksson AE, Jones TA, Lilsjas A. 1986. Zinc enzymes. In: Bertini I, Luchinat C, Maret W, Zeppezauer M, eds. Progress in inorganic biochemistry and biophysics. Vol. 1. Cambridge, MA: Burkhauser. pp 317-328.
  3. [82]82. Wallace A. 1996. The role of His in metal binding sites. Chapter 7 [PhD thesis]. Am Chem Soc 112:4759-4767.
  4. [88]88. 1469896x, 1998, 8, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/pro.5560070805, Wiley Online Library on [15/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

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Authors
Alberts, I. L., Nadassy, K., & Wodak, S. J.
Affiliations
  • University of Stirling (GB)
  • European Bioinformatics Institute (GB)
Corresponding author
Wodak, Shoshana J.
Venue
Protein Science
Publisher
Wiley
Published
1998-08
Volume
7
Issue
8
Pages
1700-1716
ISSN
  • 0961-8368 (ISSN-L)
  • 1469-896X
OpenAlex
W2148386309
Cited by
423
References
93
Citations by year
2026: 6 · 2025: 7 · 2024: 8 · 2023: 10 · 2022: 10 · 2021: 11 · 2020: 11 · 2019: 11 · 2018: 11 · 2017: 13 · 2016: 18 · 2015: 16 · 2014: 19 · 2013: 11 · 2012: 23
FWCI
14.55
Type
journal article
Language
en
Open access
Locations
  • Protein Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Dépôt institutionnel de l'Université libre de Bruxelles (Université Libre de Bruxelles) (submittedVersion)
Funders
  • European Bioinformatics Institute
  • University of Stirling
Topics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Chemistry › Inorganic Chemistry › Crystal structures of chemical compounds
Keywords
zinc binding site, zinc coordination geometry, primary coordination sphere, endopeptidase, hydrophobic residues, Protein Data Bank
MeSH terms
Aspartic Acid, Binding Sites, Catalysis, Chlorine, Cysteine, Glutamine, Histidine, Models, Molecular, Molecular Conformation, Nitrogen, Oxygen, Protein Binding, Sulfur, Zinc, Databases, Factual, Crystallography, X-Ray

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