Structure of Human RNase H1 Complexed with an RNA/DNA Hybrid: Insight into HIV Reverse Transcription
Open accessAbstract
We report here crystal structures of human RNase H1 complexed with an RNA/DNA substrate. Unlike B. halodurans RNase H1, human RNase H1 has a basic protrusion, which forms a DNA-binding channel and together with the conserved phosphate-binding pocket confers specificity for the B form and 2'-deoxy DNA. The RNA strand is recognized by four consecutive 2'-OH groups and cleaved by a two-metal ion mechanism. Although RNase H1 is overall positively charged, the substrate interface is neutral to acidic in character, which likely contributes to the catalytic specificity. Positions of the scissile phosphate and two catalytic metal ions are interdependent and highly coupled. Modeling of HIV reverse transcriptase (RT) with RNA/DNA in its RNase H active site suggests that the substrate cannot simultaneously occupy the polymerase active site and must undergo a conformational change to toggle between the two catalytic centers. The region that accommodates this conformational change offers a target to develop HIV-specific inhibitors.
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RNase H proteins bind the minor groove of an RNA-DNA hybrid.
“RNase H proteins bind the minor groove of an RNA-DNA hybrid (Nowotny et al. 2007).”
From Ribonucleotide errors, RNase HII, and ribonucleotide excision repair (2026) · cites this paper as Nowotny et al. 2007
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Ribonucleotide errors, RNase HII, and ribonucleotide excision repair
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“RNase H proteins bind the minor groove of an RNA-DNA hybrid (Nowotny et al. 2007).”
Influential
- Authors
- Nowotny, M., Gaidamakov, S. A., Ghirlando, R., Cerritelli, S. M., Crouch, R. J., & Yang, W.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Yang, Wei
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2007-10
- Volume
- 28
- Issue
- 2
- Pages
- 264-276
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2144029907
- Cited by
- 316
- References
- 5
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 17 · 2023: 12 · 2022: 26 · 2021: 23 · 2020: 19 · 2019: 17 · 2018: 12 · 2017: 19 · 2016: 5 · 2015: 14 · 2014: 25 · 2013: 21 · 2012: 16
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Child Health and Human Development
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases
- Topics
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
- Keywords
- RNase H1, HIV reverse transcriptase, RNA-DNA hybrids, crystal structure, two-metal-ion mechanism, scissile phosphate, catalytic metal ions, conformational change, substrate recognition
- MeSH terms
- Amino Acid Sequence, Calcium, Crystallography, DNA, DNA-Binding Proteins, HIV, Humans, Magnesium, Manganese, Models, Molecular, Molecular Sequence Data, Nucleic Acid Conformation, Protein Conformation, RNA-Directed DNA Polymerase, RNA, Substrate Specificity, Surface Properties, RNA-Binding Proteins, Ribonuclease H, Reverse Transcriptase Inhibitors, Catalytic Domain, Reverse Transcription
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