Structure-Based Design of Transcription Factors
Abstract
Computer modeling suggested that transcription factors with novel sequence specificities could be designed by combining known DNA binding domains. This structure-based strategy was tested by construction of a fusion protein, ZFHD1, that contained zinc fingers 1 and 2 from Zif268, a short polypeptide linker, and the homeodomain from Oct-1. The fusion protein bound optimally to a sequence containing adjacent homeodomain (TAATTA) and zinc finger (NGGGNG) subsites. When fused to an activation domain, ZFHD1 regulated promoter activity in vivo in a sequence-specific manner. Analysis of known protein-DNA complexes suggests that many other DNA binding proteins could be designed in a similar fashion.
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Previous studies created chimeric transcription factors recognizing synthetic elements or used phage display to create zinc finger proteins.
“Previous studies have either created chimeric transcription factors which recognize synthetic regulatory elements by fusing domains from biologically unrelated proteins, or used phage display technology to create a zinc finger protein which recognizes a DNA site generated by a chromosomal translocation”
From Assembly requirements of PU.1–Pip (IRF‐4) activator complexes: inhibiting function in vivo using fused dimers (1999) · cites this paper as Pomerantz et al., 1995
The selectivity of a chimeric transcription factor depends on intermediate affinity and high specificity of isolated subdomains.
“This is consistent with the overall selectivity of a chimeric transcription factor depending on the intermediate affinity and high specificity of the isolated sub-domains”
From Assembly requirements of PU.1–Pip (IRF‐4) activator complexes: inhibiting function in vivo using fused dimers (1999) · cites this paper as Pomerantz et al., 1995
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Bearne, S. L., & Wolfenden, R. V. (1997) · Biochemistry · doi:10.1021/bi9620722 · Cited by 61 · see citing works
Structure-Based Design of a Dimeric Zinc Finger Protein
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Self-citationQuantum Mechanical Design of Enzyme Active Sites
Zhang, X., DeChancie, J., Günaydin, H., Chowdry, A. B., Clemente, F. R., Smith, Handel, T. M., & Houk, K. N. (2008) · The Journal of Organic Chemistry · doi:10.1021/jo701974n · Cited by 58 · see citing works
Absence of microclimate selectivity in insectivorous birds of the Neotropical forest understory
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“Next, we used ZFHD1–NFZ to inducibly express the human hepatocyte growth factor (HGF) gene (2.2 kb) 80–84 and observed a rapamycin dose-dependent increase in secreted HGF protein, with minimal leakiness in untreated cells (Fig.”
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POU domain transcription factors in embryonic development
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Pharmacologic control of a humanized gene therapy system implanted into nude mice.
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“pCGNN-ZFHD1-3hFKBP and the retroviral vector SMTN-ZFHD1-3hFKBP express the ZFHD1 DNA binding domain (5) fused to three copies of hFKBP.”
BackgroundMethodInfluentialArtificial mammalian gene regulation networks-novel approaches for gene therapy and bioengineering.
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A Search for Single Substitutions That Eliminate Enzymatic Function in a Bacterial Ribonuclease
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Covalent Attachment of Arc Repressor Subunits by a Peptide Linker Enhances Affinity for Operator DNA
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Design of TATA box-binding protein/zinc finger fusions for targeted regulation of gene expression
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- Authors
- Pomerantz, J. L., Sharp, P. A., & Pabo, C. O.
- Affiliations
- Harvard–MIT Division of Health Sciences and Technology (US)
- Massachusetts Institute of Technology (US)
- Venue
- Science
- Published
- 1995-01-06
- Volume
- 267
- Issue
- 5194
- Pages
- 93-96
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2022704908
- Cited by
- 226
- References
- 18
- Citations by year
- 2025: 3 · 2024: 2 · 2023: 1 · 2022: 2 · 2019: 1 · 2018: 2 · 2017: 4 · 2015: 2 · 2014: 3 · 2013: 2 · 2012: 2
- FWCI
- 9.14
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA042063, P30CA014051)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- structure-based protein design, DNA-binding domain, zinc finger, homeodomain, Zif268, Oct-1, fusion protein, sequence specificity, protein-DNA complex, promoter regulation, transactivation domain
- MeSH terms
- Amino Acid Sequence, Base Sequence, Binding Sites, Cloning, Molecular, Computer Simulation, DNA-Binding Proteins, Gene Expression Regulation, Models, Molecular, Molecular Sequence Data, Promoter Regions, Genetic, Recombinant Fusion Proteins, Transcription Factors, Transfection, Protein Engineering, Zinc Fingers, Homeodomain Proteins, Octamer Transcription Factor-1, Host Cell Factor C1
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