Structural studies of the ArsD arsenic metallochaperone using molecular dynamics

T. Shilpa, Barry P. Rosen, A. Abdul Ajees

Research output: Contribution to journalArticle

Abstract

Over the past three decades the occurrence of high environmental concentrations of arsenic has been recognized as a major public health concern. Arsenic is a carcinogen and causative agent for number of diseases. The toxic and carcinogenic effects of arsenic are the result of inactivation of specific enzymes of metabolism, induction of oxidative stress, inhibition of DNA repair mechanisms and deregulation of cell proliferation. Despite its toxicity, arsenic has a long history of usage as chemotherapeutic agent. Today, drugs containing arsenic (and the related metalloid antimony) are used for treating acute promyelocytic leukemia and diseases caused by protozoan parasites. In response to its toxicity, many microorganisms have developed arsenic resistance mechanism. In bacteria, arsenic resistance genes are organized in ars operons. The best characterized, the ars operon from Escherichia coli plasmid R773, has five genes, arsRDABC. ArsC is a reductase that reduces inorganic As(V) to As(III). ArsR is a 117-residue homodimeric As(III)-responsive transcriptional repressor with high affinity for the ars promoter. ArsA is an ATPase, which is the catalytic subunit of the ArsAB efflux pump, and ArsD is an As(III) chaperone to the ArsAB pump. ArsD is a homodimer of two 120-residue subunits with three vicinal cysteine pairs, Cys12-Cys13, Cys112-Cys113 and Cys119-Cys120. A fully-active truncated version of ArsD protein with 109 residues (ArsD109) has been crystallized, and the structure has been solved using X-ray crystallography. Biochemical studies suggested that wild-type ArsD binds three As(III) per monomer, while the derivative with a truncation at residue 109 binds only a single As(III). To understand the secondary structure and folding of the C-terminus of ArsD, which includes two cysteine pairs Cys112-Cys113 and Cys119-Cys120, Molecular Dynamics (MD) simulations were employed using AMBER software in presence or absence of arsenite [As(III)] ligand.

Original languageEnglish
Pages (from-to)227-233
Number of pages7
JournalJournal of Computational Methods in Sciences and Engineering
Volume17
Issue number2
DOIs
Publication statusPublished - 01-01-2017

Fingerprint

Arsenic
Molecular Dynamics
Molecular dynamics
Toxicity
Pump
Oxidative Stress
Gene
Cell Proliferation
Microorganisms
ATP Synthase
Leukemia
Public Health
Secondary Structure
Folding
Promoter
Truncation
Acute
Bacteria
Metabolism
Escherichia Coli

All Science Journal Classification (ASJC) codes

  • Engineering(all)
  • Computer Science Applications
  • Computational Mathematics

Cite this

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abstract = "Over the past three decades the occurrence of high environmental concentrations of arsenic has been recognized as a major public health concern. Arsenic is a carcinogen and causative agent for number of diseases. The toxic and carcinogenic effects of arsenic are the result of inactivation of specific enzymes of metabolism, induction of oxidative stress, inhibition of DNA repair mechanisms and deregulation of cell proliferation. Despite its toxicity, arsenic has a long history of usage as chemotherapeutic agent. Today, drugs containing arsenic (and the related metalloid antimony) are used for treating acute promyelocytic leukemia and diseases caused by protozoan parasites. In response to its toxicity, many microorganisms have developed arsenic resistance mechanism. In bacteria, arsenic resistance genes are organized in ars operons. The best characterized, the ars operon from Escherichia coli plasmid R773, has five genes, arsRDABC. ArsC is a reductase that reduces inorganic As(V) to As(III). ArsR is a 117-residue homodimeric As(III)-responsive transcriptional repressor with high affinity for the ars promoter. ArsA is an ATPase, which is the catalytic subunit of the ArsAB efflux pump, and ArsD is an As(III) chaperone to the ArsAB pump. ArsD is a homodimer of two 120-residue subunits with three vicinal cysteine pairs, Cys12-Cys13, Cys112-Cys113 and Cys119-Cys120. A fully-active truncated version of ArsD protein with 109 residues (ArsD109) has been crystallized, and the structure has been solved using X-ray crystallography. Biochemical studies suggested that wild-type ArsD binds three As(III) per monomer, while the derivative with a truncation at residue 109 binds only a single As(III). To understand the secondary structure and folding of the C-terminus of ArsD, which includes two cysteine pairs Cys112-Cys113 and Cys119-Cys120, Molecular Dynamics (MD) simulations were employed using AMBER software in presence or absence of arsenite [As(III)] ligand.",
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Structural studies of the ArsD arsenic metallochaperone using molecular dynamics. / Shilpa, T.; Rosen, Barry P.; Ajees, A. Abdul.

In: Journal of Computational Methods in Sciences and Engineering, Vol. 17, No. 2, 01.01.2017, p. 227-233.

Research output: Contribution to journalArticle

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