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Cited by 9Plant biochemistry and biosynthesisProtein Kinase Regulation and GTPase SignalingEnzyme Structure and Function

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Structural Insight into Geranylgeranyl Diphosphate Synthase (GGDPS) for Cancer Therapy

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Pham, Andrew C., Holstein, Sarah A., Borgstahl, Gloria E.O.·2024·Molecular Cancer Therapeutics
DOI 10.1158/1535-7163.mct-23-0358PMC PMC10762340

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Abstract

Geranylgeranyl diphosphate synthase (GGDPS), the source of the isoprenoid donor in protein geranylgeranylation reactions, has become an attractive target for anticancer therapy due to the reliance of cancers on geranylgeranylated proteins. Current GGDPS inhibitor development focuses on optimizing the drug-target enzyme interactions of nitrogen-containing bisphosphonate-based drugs. To advance GGDPS inhibitor development, understanding the enzyme structure, active site, and ligand/product interactions is essential. Here we provide a comprehensive structure-focused review of GGDPS. We reviewed available yeast and human GGDPS structures and then used AlphaFold modeling to complete unsolved structural aspects of these models. We delineate the elements of higher-order structure formation, product-substrate binding, the electrostatic surface, and small-molecule inhibitor binding. With the rise of structure-based drug design, the information provided here will serve as a valuable tool for rationally optimizing inhibitor selectivity and effectiveness.

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Figure 1. The substrate binding sites (IPP and FDP). Residues found within 4 Å of the GGDPS substrates in yeast (cyan) and human (green) are represented as sticks. The human AF 2Q80 and IPP-FDP bound yGGDPS structures were used (PDB: 2E8T). A, The IPP binding site (site 1). hGGDPSAF overlaid on top of the IPP-FDP bound yGGDPS shows amino acid residues within 4 Å of the IPP substrate are highly conserved. Individual residues for yGGDPS IPP binding and the corresponding hGGDPSAF IPP binding sites are shown in the following columns. B, The FDP binding site (site 2). hGGDPSAF overlaid on top of the IPP-FDP bound yGGDPS shows amino acid residues within 4 Å of the FDP substrate are highly conserved. Individual residues for yGGDPS FDP binding and the corresponding hGGDPSAF FDP binding sites are shown in the following columns. Mg2+ ions are represented as magenta spheres with positions taken from the hGGDPSAF structure.
Figure 1. The substrate binding sites (IPP and FDP). Residues found within 4 Å of the GGDPS substrates in yeast (cyan) and human (green) are represented as sticks. The human AF 2Q80 and IPP-FDP bound yGGDPS structures were used (PDB: 2E8T). A, The IPP binding site (site 1). hGGDPSAF overlaid on top of the IPP-FDP bound yGGDPS shows amino acid residues within 4 Å of the IPP substrate are highly conserved. Individual residues for yGGDPS IPP binding and the corresponding hGGDPSAF IPP binding sites are shown in the following columns. B, The FDP binding site (site 2). hGGDPSAF overlaid on top of the IPP-FDP bound yGGDPS shows amino acid residues within 4 Å of the FDP substrate are highly conserved. Individual residues for yGGDPS FDP binding and the corresponding hGGDPSAF FDP binding sites are shown in the following columns. Mg2+ ions are represented as magenta spheres with positions taken from the hGGDPSAF structure.CC BY-NC-ND · PubMed Central
Figure 2. The product-binding sites (GGDP and GGDPi). The GGDP binding site (site 3). Residues found within 4 Å of the GGDPS product in its classical and inhibitory site in yeast (cyan) and human (green) are represented as sticks. The human AF 2Q80 and GGDP bound yGGDPS structures were used (PDB: 2E8V and 2Z4V). A, The classical GGDP binding site (site 3). hGGDPSAF overlaid on top of the classically GGDP bound yGGDPS shows amino acid residues within 4 Å of the GGDP product are highly conserved. Individual residues for yGGDPS classical GGDP binding and the corresponding hGGDPSAF GGDP binding sites are shown in the following columns. B, The GGDP inhibitory (GGDPi) binding site (site 4). hGGDPSAF bound at the inhibitory GGDP site overlaid on top of the inhibitory GGDP bound yGGDPS. 18/24 (75%) of the residues found to be within 4 Å of the GGDPi product in either yGGDPS or hGGDPS were completely conserved suggesting high conservation of product-binding residues. Individual residues for GGDPi yGGDPS and GGDPi hGGDPS binding are shown in the following columns. Mg2+ ions are represented as purple spheres in the yGGDPS structure and as magenta spheres in the hGGDPSAF structure.
Figure 2. The product-binding sites (GGDP and GGDPi). The GGDP binding site (site 3). Residues found within 4 Å of the GGDPS product in its classical and inhibitory site in yeast (cyan) and human (green) are represented as sticks. The human AF 2Q80 and GGDP bound yGGDPS structures were used (PDB: 2E8V and 2Z4V). A, The classical GGDP binding site (site 3). hGGDPSAF overlaid on top of the classically GGDP bound yGGDPS shows amino acid residues within 4 Å of the GGDP product are highly conserved. Individual residues for yGGDPS classical GGDP binding and the corresponding hGGDPSAF GGDP binding sites are shown in the following columns. B, The GGDP inhibitory (GGDPi) binding site (site 4). hGGDPSAF bound at the inhibitory GGDP site overlaid on top of the inhibitory GGDP bound yGGDPS. 18/24 (75%) of the residues found to be within 4 Å of the GGDPi product in either yGGDPS or hGGDPS were completely conserved suggesting high conservation of product-binding residues. Individual residues for GGDPi yGGDPS and GGDPi hGGDPS binding are shown in the following columns. Mg2+ ions are represented as purple spheres in the yGGDPS structure and as magenta spheres in the hGGDPSAF structure.CC BY-NC-ND · PubMed Central
Figure 3. Overlay of published ligand-bound GGDPS structures in the hGGDPSAF active site. A, Overlay of the substrates (IPP and FDP) and product (both GGDP and GGDPi sites). B, Overlay of the yGGDPS structure compounds from Chen / Zhang and colleagues in the hGGDPS active site. PDB codes and color are as follows: 2E91 (cyan), 2E92 (brown), 2E93 (sea foam green), 2E94 (light blue), 2E95 (forest green), 2ZEU (dark gray). Bisphosphonate compounds are labeled on the basis of their numbers used in the text. Zoledronic acid (ZOL) and minodronate (MIN) are also abbreviated in the figure. C, Overlay of the compounds coming from Guo and colleagues. PDB codes and colors: 2Z4W (salmon), 2Z4Y (teal), 2Z4Z (purple), 2Z50 (brick red), 2Z52 (gold), 2Z7I (tan), 2Z78 (magenta). Structures were solved with the yGGDPS enzyme and overlaid onto the hGGDPSAF active site. Bisphosphonate compounds are labeled on the basis of the number and abbreviations used in the text (DGBP). D, Overlay of compounds from solved drug-bound hGGDPS structures. FV0109 is the thienopyrimidine-based bisphosphonate investigated by Lacbay and coworkers (PDB: 6C57, pink). Structures of zoledronate (ZOL) and ibandronate (IBN) were solved by Lisnyansky and colleagues. PDB codes are: 6G31 (cyan), 6R4V (dark blue).
Figure 3. Overlay of published ligand-bound GGDPS structures in the hGGDPSAF active site. A, Overlay of the substrates (IPP and FDP) and product (both GGDP and GGDPi sites). B, Overlay of the yGGDPS structure compounds from Chen / Zhang and colleagues in the hGGDPS active site. PDB codes and color are as follows: 2E91 (cyan), 2E92 (brown), 2E93 (sea foam green), 2E94 (light blue), 2E95 (forest green), 2ZEU (dark gray). Bisphosphonate compounds are labeled on the basis of their numbers used in the text. Zoledronic acid (ZOL) and minodronate (MIN) are also abbreviated in the figure. C, Overlay of the compounds coming from Guo and colleagues. PDB codes and colors: 2Z4W (salmon), 2Z4Y (teal), 2Z4Z (purple), 2Z50 (brick red), 2Z52 (gold), 2Z7I (tan), 2Z78 (magenta). Structures were solved with the yGGDPS enzyme and overlaid onto the hGGDPSAF active site. Bisphosphonate compounds are labeled on the basis of the number and abbreviations used in the text (DGBP). D, Overlay of compounds from solved drug-bound hGGDPS structures. FV0109 is the thienopyrimidine-based bisphosphonate investigated by Lacbay and coworkers (PDB: 6C57, pink). Structures of zoledronate (ZOL) and ibandronate (IBN) were solved by Lisnyansky and colleagues. PDB codes are: 6G31 (cyan), 6R4V (dark blue).CC BY-NC-ND · PubMed Central

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Metadata

Authors
Pham, A. C., Holstein, S. A., & Borgstahl, G. E. O.
Affiliations
University of Nebraska Medical Center (US)
Corresponding author
Borgstahl, Gloria E.O.
ORCID
Venue
Molecular Cancer Therapeutics
Publisher
American Association for Cancer Research (AACR)
Published
2023-09-26
Volume
23
Issue
1
Pages
14-23
ISSN
  • 1535-7163 (ISSN-L)
  • 1538-8514
DOI
10.1158/1535-7163.mct-23-0358
PMC
PMC10762340
OpenAlex
W4387089883
Cited by
9
References
1
Citations by year
2026: 4 · 2025: 4 · 2024: 1
FWCI
0.24
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Cancer Therapeutics (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Cancer Institute (R01CA258621, P30CA036727)
  • U.S. Department of Education (P200A210032)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Plant biochemistry and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Structural Biology › Enzyme Structure and Function
Keywords
geranylgeranyl diphosphate synthase, protein geranylgeranylation, isoprenoid metabolism, anticancer drug targets, enzyme structure, active site, electrostatic surface, structure-based drug design
MeSH terms
Enzyme Inhibitors, Humans, Neoplasms, Terpenes, Protein Prenylation, Farnesyltranstransferase

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