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Cited by 1,057Computational Drug Discovery MethodsProtein Structure and DynamicsEnzyme Structure and Function

Anatomy of protein pockets and cavities: Measurement of binding site geometry and implications for ligand design

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Liang, Jie, Woodward, Clare, Edelsbrunner, Herbert·1998·Protein Science
DOI 10.1002/pro.5560070905PMC PMC2144175
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Abstract

Identification and size characterization of surface pockets and occluded cavities are initial steps in protein structure‐based ligand design. A new program, CAST, for automatically locating and measuring protein pockets and cavities, is based on precise computational geometry methods, including alpha shape and discrete flow theory. CAST identifies and measures pockets and pocket mouth openings, as well as cavities. The program specifies the atoms lining pockets, pocket openings, and buried cavities; the volume and area of pockets and cavities; and the area and circumference of mouth openings. CAST analysis of over 100 proteins has been carried out; proteins examined include a set of 51 monomeric enzyme‐ligand structures, several elastase‐inhibitor complexes, the FK506 binding protein, 30 HIV‐1 protease‐inhibitor complexes, and a number of small and large protein inhibitors. Medium‐sized globular proteins typically have 10‐20 pockets/cavities. Most often, binding sites are pockets with 1‐2 mouth openings; much less frequently they are cavities. Ligand binding pockets vary widely in size, most within the range 10 2 ‐10 3 Å 3 . Statistical analysis reveals that the number of pockets and cavities is correlated with protein size, but there is no correlation between the size of the protein and the size of binding sites. Most frequently, the largest pocket/cavity is the active site, but there are a number of instructive exceptions. Ligand volume and binding site volume are somewhat correlated when binding site volume is < 700 Å 3 , but the ligand seldom occupies the entire site. Auxiliary pockets near the active site have been suggested as additional binding surface for designed ligands (Mattos C et al., 1994, Nat Struct Bid 1 :55‐58). Analysis of elastase‐inhibitor complexes suggests that CAST can identify ancillary pockets suitable for recruitment in ligand design strategies. Analysis of the FK506 binding protein, and of compounds developed in SAR by NMR (Shuker SB et al., 1996, Science 274:1531‐1534), indicates that CAST pocket computation may provide a priori identification of target proteins for linked‐fragment design. CAST analysis of 30 HIV‐1 protease‐inhibitor complexes shows that the flexible active site pocket can vary over a range of 853‐1,566 Å 3 , and that there are two pockets near or adjoining the active site that may be recruited for ligand design.

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  • This volume range is within the 100-800 Å3 range commonly seen in protein binding pockets or cavities.

    “which is within the range (100 - 800 Å3) commonly observed in protein binding pockets or cavities (62).”

    From Comparative Analysis of Homology Models of the Ah Receptor Ligand Binding Domain: Verification of Structure–Function Predictions by Site-Directed Mutagenesis of a Nonfunctional Receptor (2013) · cites this paper as [62]

    In “Pockets and cavities with known ligands” (page unavailable), the paper says most ligand-binding sites in its set of monomeric enzymes are on the order of 100–1,000 ų. That supports the general scale, but not the more specific claim that 100–800 ų is the commonly observed range. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • CASTp indicated a buried cavity in the core of the modeled mAhR PAS B domain with a volume of 496 Å3, which falls in the observed range of 100-800 Å3 for protein binding pockets or cavities.

    “The analysis of structural pockets and cavities, performed by the CASTp server, indicated the presence of a buried cavity in the core of the modeled domain, with a volume of 496 Å 3 , which falls in the observed range (100-800 Å 3 ) for protein binding pockets or cavities (62).”

    From Structural and Functional Characterization of the Aryl Hydrocarbon Receptor Ligand Binding Domain by Homology Modeling and Mutational Analysis (2007) · cites this paper as [62]

    In “Pockets and cavities with known ligands” (page unavailable), the paper says most ligand-binding sites in its monomeric-enzyme set are on the order of 10²–10³ ų, which includes 496 ų. It does not give the cited range of 100–800 ų. The citation supports the general size comparison, but not that specific upper bound; the modeled mAhR cavity measurement is the citing authors’ own result. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

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Authors
Liang, J., Woodward, C., & Edelsbrunner, H.
Affiliations
  • University of Minnesota (US)
  • University of Illinois Urbana-Champaign (US)
Corresponding author
Woodward, Clare
ORCID
Venue
Protein Science
Publisher
Wiley
Published
1998-09
Volume
7
Issue
9
Pages
1884-1897
ISSN
  • 0961-8368 (ISSN-L)
  • 1469-896X
DOI
10.1002/pro.5560070905
PMC
PMC2144175
OpenAlex
W2105902442
Cited by
1,057
References
60
Citations by year
2026: 22 · 2025: 32 · 2024: 28 · 2023: 19 · 2022: 27 · 2021: 39 · 2020: 27 · 2019: 24 · 2018: 43 · 2017: 28 · 2016: 48 · 2015: 32 · 2014: 45 · 2013: 53 · 2012: 54
FWCI
17.61
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3774 d)
Locations
  • Protein Science (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Science Foundation
  • National Institutes of Health (5r01gm026242-20)
  • National Institute of General Medical Sciences (GM26242)
Topics
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
Keywords
protein binding sites, protein pockets, protein cavities, alpha shapes, ligand design, structure-based drug design, FKBP, active site flexibility
MeSH terms
Algorithms, Bacterial Proteins, Binding Sites, Enzymes, Ligands, Models, Molecular, Proteins, Software, Protein Structure, Tertiary

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