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Article ; Online: A conserved polar residue plays a critical role in mismatch detection in A-family DNA polymerases.

Clement, Patterson C / Sapam, Tuleshwori / Nair, Deepak T

International journal of biological macromolecules

2024 , Page(s) 131965

Abstract: In A-family DNA polymerases (dPols), a functional 3'-5' exonuclease activity is known to proofread newly synthesized DNA. The identification of a mismatch in substrate DNA leads to transfer of the primer strand from the polymerase active site to the ... ...

Abstract	In A-family DNA polymerases (dPols), a functional 3'-5' exonuclease activity is known to proofread newly synthesized DNA. The identification of a mismatch in substrate DNA leads to transfer of the primer strand from the polymerase active site to the exonuclease active site. To shed more light regarding the mechanism responsible for the detection of mismatches, we have utilized DNA polymerase 1 from Aquifex pyrophilus (ApPol1). The enzyme synthesized DNA with high fidelity and exhibited maximal exonuclease activity with DNA substrates bearing mismatches at the -2 and - 3 positions. The crystal structure of apo-ApPol1 was utilized to generate a computational model of the functional ternary complex of this enzyme. The analysis of the model showed that N332 forms interactions with minor groove atoms of the base pairs at the -2 and - 3 positions. The majority of known A-family dPols show the presence of Asn at a position equivalent to N332. The N332L mutation led to a decrease in the exonuclease activity for representative purine-pyrimidine, and pyrimidine-pyrimidine mismatches at -2 and - 3 positions, respectively. Overall, our findings suggest that conserved polar residues located towards the minor groove may facilitate the detection of position-specific mismatches to enhance the fidelity of DNA synthesis.
Language	English
Publishing date	2024-04-30
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2024.131965
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Article ; Online: Pfprex from Plasmodium falciparum can bypass oxidative stress-induced DNA lesions.

Sharma, Minakshi / Nair, Deepak T

The FEBS journal

2022 Volume 289, Issue 17, Page(s) 5218–5240

Abstract: Apicomplexans such as the malaria parasite Plasmodium falciparum possess a unique organelle known as the apicoplast that has its own circular genome. The apicoplast genome is AT rich and is subjected to oxidative stress from the byproducts of the normal ... ...

Abstract	Apicomplexans such as the malaria parasite Plasmodium falciparum possess a unique organelle known as the apicoplast that has its own circular genome. The apicoplast genome is AT rich and is subjected to oxidative stress from the byproducts of the normal biochemical pathways that operate in the apicoplast. It is expected that oxidative stress will lead to the appearance of DNA lesions such as 2-hydroxydeoxyadenine, thymine glycol, and 8-oxodeoxyguanine in the apicoplast genome. The apicoplast genome is replicated by the DNA polymerase activity present in the Pfprex enzyme. We have named the polymerase module of Pfprex as PfpPol and the enzyme belongs to the A family of DNA polymerases. Similar to other members of this family, PfpPol also exhibits high fidelity of DNA synthesis. We show that this enzyme is also capable of carrying out translesion DNA synthesis past common DNA lesions that arise due to oxidative stress. The residues N505 and Y509 from the fingers sub-domain, which are unique to PfpPol, play an important role in the ability of PfpPol to bypass the three lesions. The observed lesion-bypass ability of the Pfprex enzyme will minimize the adverse effects of oxidative stress on the apicoplast genome of the malaria parasite. These findings also have implications regarding the evolution of the machinery responsible for replication of organellar genomes.
MeSH term(s)	Apicoplasts/genetics ; Apicoplasts/metabolism ; DNA/metabolism ; Humans ; Malaria/metabolism ; Oxidative Stress/genetics ; Plasmodium falciparum ; Protozoan Proteins/metabolism
Chemical Substances	Protozoan Proteins ; DNA (9007-49-2)
Language	English
Publishing date	2022-03-11
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16414
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Article: Pfprex from Plasmodium falciparum can bypass oxidative stress‐induced DNA lesions

Sharma, Minakshi / Nair, Deepak T.

FEBS journal. 2022 Sept., v. 289, no. 17

2022

Abstract	Apicomplexans such as the malaria parasite Plasmodium falciparum possess a unique organelle known as the apicoplast that has its own circular genome. The apicoplast genome is AT rich and is subjected to oxidative stress from the byproducts of the normal biochemical pathways that operate in the apicoplast. It is expected that oxidative stress will lead to the appearance of DNA lesions such as 2‐hydroxydeoxyadenine, thymine glycol, and 8‐oxodeoxyguanine in the apicoplast genome. The apicoplast genome is replicated by the DNA polymerase activity present in the Pfprex enzyme. We have named the polymerase module of Pfprex as PfpPol and the enzyme belongs to the A family of DNA polymerases. Similar to other members of this family, PfpPol also exhibits high fidelity of DNA synthesis. We show that this enzyme is also capable of carrying out translesion DNA synthesis past common DNA lesions that arise due to oxidative stress. The residues N505 and Y509 from the fingers sub‐domain, which are unique to PfpPol, play an important role in the ability of PfpPol to bypass the three lesions. The observed lesion‐bypass ability of the Pfprex enzyme will minimize the adverse effects of oxidative stress on the apicoplast genome of the malaria parasite. These findings also have implications regarding the evolution of the machinery responsible for replication of organellar genomes.
Keywords	DNA ; DNA replication ; DNA-directed DNA polymerase ; Plasmodium falciparum ; apicoplast genome ; evolution ; malaria ; oxidative stress ; parasites ; thymine
Language	English
Dates of publication	2022-09
Size	p. 5218-5240.
Publishing place	John Wiley & Sons, Ltd
Document type	Article
Note	JOURNAL ARTICLE
ZDB-ID	2173655-8
ISSN	1742-4658 ; 1742-464X
ISSN (online)	1742-4658
ISSN	1742-464X
DOI	10.1111/febs.16414
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Article ; Online: The PHP domain of PolX from Staphylococcus aureus aids high fidelity DNA synthesis through the removal of misincorporated deoxyribo-, ribo- and oxidized nucleotides.

Nagpal, Shilpi / Nair, Deepak T

Scientific reports

2021 Volume 11, Issue 1, Page(s) 4178

Abstract: The X family is one of the eight families of DNA polymerases (dPols) and members of this family are known to participate in the later stages of Base Excision Repair. Many prokaryotic members of this family possess a Polymerase and Histidinol Phosphatase ( ...

Abstract	The X family is one of the eight families of DNA polymerases (dPols) and members of this family are known to participate in the later stages of Base Excision Repair. Many prokaryotic members of this family possess a Polymerase and Histidinol Phosphatase (PHP) domain at their C-termini. The PHP domain has been shown to possess 3'-5' exonuclease activity and may represent the proofreading function in these dPols. PolX from Staphylococcus aureus also possesses the PHP domain at the C-terminus, and we show that this domain has an intrinsic Mn
MeSH term(s)	Amino Acid Sequence ; Catalytic Domain/genetics ; DNA/genetics ; DNA Repair/genetics ; DNA Replication/genetics ; DNA-Directed DNA Polymerase/genetics ; Exodeoxyribonucleases/genetics ; Histidinol-Phosphatase/genetics ; Hydrolases/genetics ; Nucleotides/genetics ; Staphylococcus aureus/genetics
Chemical Substances	Nucleotides ; DNA (9007-49-2) ; DNA-Directed DNA Polymerase (EC 2.7.7.7) ; Hydrolases (EC 3.-) ; Exodeoxyribonucleases (EC 3.1.-) ; Histidinol-Phosphatase (EC 3.1.3.15)
Language	English
Publishing date	2021-02-18
Publishing country	England
Document type	Journal Article
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-021-83498-1
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Article: Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs

Narayanan, Naveen / Nair, Deepak T

International journal of biological macromolecules. 2021 Jan. 31, v. 168

2021

Abstract: SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3′ to 5′ exoribonuclease activity responsible for removing mismatches that arise during genome ...

Abstract	SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3′ to 5′ exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3′ nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
Keywords	COVID-19 infection ; RNA ; Severe acute respiratory syndrome coronavirus 2 ; active sites ; antiretroviral agents ; binding sites ; computer simulation ; enzyme activity ; enzyme inhibition ; enzyme inhibitors ; exoribonucleases ; gene duplication ; sequence homology ; viral genome ; viral nonstructural proteins
Language	English
Dates of publication	2021-0131
Size	p. 272-278.
Publishing place	Elsevier B.V.
Document type	Article
Note	golden set
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2020.12.038
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Article ; Online: Vitamin B12 may inhibit RNA-dependent-RNA polymerase activity of nsp12 from the SARS-CoV-2 virus.

Narayanan, Naveen / Nair, Deepak T

IUBMB life

2020 Volume 72, Issue 10, Page(s) 2112–2120

Abstract: SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 ... ...

Abstract	SARS-CoV-2 is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. Like other members of this family, the virus possesses a positive-sense single-stranded RNA genome. The genome encodes for the nsp12 protein, which houses the RNA-dependent-RNA polymerase (RdRP) activity responsible for the replication of the viral genome. A homology model of nsp12 was prepared using the structure of the SARS nsp12 (6NUR) as a model. The model was used to carry out in silico screening to identify molecules among natural products, or Food and Drug Administration-approved drugs that can potentially inhibit the activity of nsp12. This exercise showed that vitamin B12 (methylcobalamin) may bind to the active site of the nsp12 protein. A model of the nsp12 in complex with substrate RNA and incoming NTP showed that vitamin B12 binding site overlaps with that of the incoming nucleotide. A comparison of the calculated energies of binding for RNA plus NTP and methylcobalamin suggested that the vitamin may bind to the active site of nsp12 with significant affinity. It is, therefore, possible that methylcobalamin binding may prevent association with RNA and NTP and thus inhibit the RdRP activity of nsp12. Overall, our computational studies suggest that methylcobalamin form of vitamin B12 may serve as an effective inhibitor of the nsp12 protein.
MeSH term(s)	Amino Acid Sequence ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; Binding Sites ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Coronavirus RNA-Dependent RNA Polymerase/chemistry ; Coronavirus RNA-Dependent RNA Polymerase/genetics ; Coronavirus RNA-Dependent RNA Polymerase/metabolism ; Genome, Viral ; High-Throughput Screening Assays ; Molecular Docking Simulation ; Molecular Dynamics Simulation ; Prescription Drugs/chemistry ; Prescription Drugs/pharmacology ; Protein Binding ; Protein Conformation, alpha-Helical ; Protein Conformation, beta-Strand ; Protein Interaction Domains and Motifs ; SARS-CoV-2/drug effects ; SARS-CoV-2/enzymology ; SARS-CoV-2/genetics ; Sequence Alignment ; Sequence Homology, Amino Acid ; Substrate Specificity ; Thermodynamics ; User-Computer Interface ; Vitamin B 12/chemistry ; Vitamin B 12/pharmacology
Chemical Substances	Antiviral Agents ; Prescription Drugs ; Coronavirus RNA-Dependent RNA Polymerase (EC 2.7.7.48) ; NSP12 protein, SARS-CoV-2 (EC 2.7.7.48) ; Vitamin B 12 (P6YC3EG204)
Keywords	covid19
Language	English
Publishing date	2020-08-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1492141-8
ISSN	1521-6551 ; 1521-6543
ISSN (online)	1521-6551
ISSN	1521-6543
DOI	10.1002/iub.2359
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Article ; Online: Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs.

Narayanan, Naveen / Nair, Deepak T

International journal of biological macromolecules

2020 Volume 168, Page(s) 272–278

Abstract: SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome ...

Abstract	SARS-CoV-2is the causative agent for the ongoing COVID19 pandemic, and this virus belongs to the Coronaviridae family. The nsp14 protein of SARS-CoV-2 houses a 3' to 5' exoribonuclease activity responsible for removing mismatches that arise during genome duplication. A homology model of nsp10-nsp14 complex was used to carry out in silico screening to identify molecules among natural products, or FDA approved drugs that can potentially inhibit the activity of nsp14. This exercise showed that ritonavir might bind to the exoribonuclease active site of the nsp14 protein. A model of the SARS-CoV-2-nsp10-nsp14 complex bound to substrate RNA showed that the ritonavir binding site overlaps with that of the 3' nucleotide of substrate RNA. A comparison of the calculated energies of binding for RNA and ritonavir suggested that the drug may bind to the active site of nsp14 with significant affinity. It is, therefore, possible that ritonavir may prevent association with substrate RNA and thus inhibit the exoribonuclease activity of nsp14. Overall, our computational studies suggest that ritonavir may serve as an effective inhibitor of the nsp14 protein. nsp14 is known to attenuate the inhibitory effect of drugs that function through premature termination of viral genome replication. Hence, ritonavir may potentiate the therapeutic properties of drugs such as remdesivir, favipiravir and ribavirin.
MeSH term(s)	Amino Acid Sequence ; Antiviral Agents/administration & dosage ; Antiviral Agents/chemistry ; Antiviral Agents/pharmacology ; COVID-19/drug therapy ; COVID-19/virology ; Catalytic Domain ; Computer Simulation ; Drug Evaluation, Preclinical ; Drug Synergism ; Drug Therapy, Combination ; Exoribonucleases/antagonists & inhibitors ; Exoribonucleases/chemistry ; Exoribonucleases/genetics ; Genome, Viral/drug effects ; Humans ; Molecular Dynamics Simulation ; Pandemics ; Ritonavir/administration & dosage ; Ritonavir/chemistry ; Ritonavir/pharmacology ; SARS-CoV-2/drug effects ; SARS-CoV-2/genetics ; SARS-CoV-2/physiology ; Viral Nonstructural Proteins/antagonists & inhibitors ; Viral Nonstructural Proteins/chemistry ; Viral Nonstructural Proteins/genetics ; Virus Replication/drug effects
Chemical Substances	Antiviral Agents ; Viral Nonstructural Proteins ; Exoribonucleases (EC 3.1.-) ; NSP14 protein, SARS-CoV-2 (EC 3.1.-) ; Ritonavir (O3J8G9O825)
Language	English
Publishing date	2020-12-09
Publishing country	Netherlands
Document type	Journal Article
ZDB-ID	282732-3
ISSN	1879-0003 ; 0141-8130
ISSN (online)	1879-0003
ISSN	0141-8130
DOI	10.1016/j.ijbiomac.2020.12.038
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Article ; Online: Antibody multispecificity: A necessary evil?

Jaiswal, Deepika / Verma, Sheenam / Nair, Deepak T / Salunke, Dinakar M

Molecular immunology

2022 Volume 152, Page(s) 153–161

Abstract: Antibodies represent key effectors of the adaptive immune system. The specificity of antibodies is an established hallmark of the immune response. However, a certain proportion of antibodies exhibit limited promiscuity or multireactivity. Germline ... ...

Abstract	Antibodies represent key effectors of the adaptive immune system. The specificity of antibodies is an established hallmark of the immune response. However, a certain proportion of antibodies exhibit limited promiscuity or multireactivity. Germline antibodies display plasticity which imparts multispecificity to enhance the antibody repertoire. Surprisingly, even affinity matured antibodies display such plasticity and multireactivity enabling their binding to more than one antigen. We propose that antibody multispecificity is a physiological requirement to expand the antibody repertoire at the germline level and to tolerate plasticity in antigens at the mature level. This property of the humoral immune response may attenuate the ability of infectious RNA viruses such as influenza, HIV and SARS-CoV-2 to acquire mutations that render resistance to neutralizing antibodies.
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; Antibodies, Neutralizing ; Antigens ; Immunity, Humoral
Chemical Substances	Antibodies, Neutralizing ; Antigens
Language	English
Publishing date	2022-11-08
Publishing country	England
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	424427-8
ISSN	1872-9142 ; 0161-5890
ISSN (online)	1872-9142
ISSN	0161-5890
DOI	10.1016/j.molimm.2022.10.012
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Article ; Online: Pyrophosphate hydrolysis is an intrinsic and critical step of the DNA synthesis reaction.

Kottur, Jithesh / Nair, Deepak T

Nucleic acids research

2018 Volume 46, Issue 12, Page(s) 5875–5885

Abstract: DNA synthesis by DNA polymerases (dPols) is central to duplication and maintenance of the genome in all living organisms. dPols catalyze the formation of a phosphodiester bond between the incoming deoxynucleoside triphosphate and the terminal primer ... ...

Abstract	DNA synthesis by DNA polymerases (dPols) is central to duplication and maintenance of the genome in all living organisms. dPols catalyze the formation of a phosphodiester bond between the incoming deoxynucleoside triphosphate and the terminal primer nucleotide with the release of a pyrophosphate (PPi) group. It is believed that formation of the phosphodiester bond is an endergonic reaction and PPi has to be hydrolyzed by accompanying pyrophosphatase enzymes to ensure that the free energy change of the DNA synthesis reaction is negative and it can proceed in the forward direction. The fact that DNA synthesis proceeds in vitro in the absence of pyrophosphatases represents a long-standing conundrum regarding the thermodynamics of the DNA synthesis reaction. Using time-resolved crystallography, we show that hydrolysis of PPi is an intrinsic and critical step of the DNA synthesis reaction catalyzed by dPols. The hydrolysis of PPi occurs after the formation of the phosphodiester bond and ensures that the DNA synthesis reaction is energetically favorable without the need for additional enzymes. Also, we observe that DNA synthesis is a two Mg2+ ion assisted stepwise associative SN2 reaction. Overall, this study provides deep temporal insight regarding the primary enzymatic reaction responsible for genome duplication.
MeSH term(s)	Crystallography, X-Ray ; DNA/biosynthesis ; DNA Polymerase beta/chemistry ; DNA Polymerase beta/metabolism ; Diphosphates/metabolism ; Escherichia coli/enzymology ; Hydrolysis ; Magnesium/chemistry ; Models, Molecular ; Nucleotides/chemistry ; Nucleotides/metabolism
Chemical Substances	Diphosphates ; Nucleotides ; DNA (9007-49-2) ; DNA Polymerase beta (EC 2.7.7.-) ; Magnesium (I38ZP9992A)
Language	English
Publishing date	2018-06-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	186809-3
ISSN	1362-4962 ; 1362-4954 ; 0301-5610 ; 0305-1048
ISSN (online)	1362-4962 ; 1362-4954
ISSN	0301-5610 ; 0305-1048
DOI	10.1093/nar/gky402
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Article ; Online: The proofreading activity of Pfprex from Plasmodium falciparum can prevent mutagenesis of the apicoplast genome by oxidized nucleotides.

Sharma, Minakshi / Narayanan, Naveen / Nair, Deepak T

Scientific reports

2020 Volume 10, Issue 1, Page(s) 11157

Abstract: The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event ...

Abstract	The DNA polymerase module of the Pfprex enzyme (PfpPol) is responsible for duplication of the genome of the apicoplast organelle in the malaria parasite. We show that PfpPol can misincorporate oxidized nucleotides such as 8oxodGTP opposite dA. This event gives rise to transversion mutations that are known to lead to adverse physiological outcomes. The apicoplast genome is particularly vulnerable to the harmful effects of 8oxodGTP due to very high AT content (~ 87%). We show that the proofreading activity of PfpPol has the unique ability to remove the oxidized nucleotide from the primer terminus. Due to this property, the proofreading domain of PfpPol is able to prevent mutagenesis of the AT-rich apicoplast genome and neutralize the deleterious genotoxic effects of ROS generated in the apicoplast due to normal metabolic processes. The proofreading activity of the Pfprex enzyme may, therefore, represent an attractive target for therapeutic intervention. Also, a survey of DNA repair pathways shows that the observed property of Pfprex constitutes a novel form of dynamic error correction wherein the repair of promutagenic damaged nucleotides is concomitant with DNA replication.
MeSH term(s)	Apicoplasts/genetics ; Apicoplasts/metabolism ; DNA Repair ; Deoxyguanine Nucleotides/metabolism ; Genome, Protozoan/genetics ; Multienzyme Complexes/metabolism ; Multienzyme Complexes/physiology ; Mutagenesis/genetics ; Nucleotides/metabolism ; Oxidation-Reduction ; Plasmodium falciparum/genetics ; Plasmodium falciparum/metabolism ; Protozoan Proteins/metabolism ; Protozoan Proteins/physiology
Chemical Substances	Deoxyguanine Nucleotides ; Multienzyme Complexes ; Nucleotides ; Protozoan Proteins ; prex protein, Plasmodium falciparum ; 8-oxodeoxyguanosine triphosphate (139307-94-1)
Language	English
Publishing date	2020-07-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-67853-2
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