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Aminoglycoside induced nephrotoxicity: molecular modeling studies of calreticulin-gentamicin complex

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Abstract

Gentamicin is a member of aminoglycoside group of broad spectrum antibiotics. It impairs protein synthesis by binding to A site of the 30S subunit of bacterial ribosomes. One of the main side effects of this drug is nephrotoxicity. The drug is known to bind to calreticulin, a chaperone essential for the folding of glycosylated proteins. We provide a detailed structural insight of the calreticulin-gentamicin complex by molecular modeling and the binding of the drug in the presence of explicit solvent was analyzed by molecular dynamics simulation. The gentamicin molecule binds to the lectin site of the calreticulin and lies in the concave channel formed by the long beta sheets. It makes interactions with residues Tyr109, Asp125, Asp135, Asp317 and Trp319 which are crucial for the chaperone function of the calreticulin. The superimposing of the modeled complex with the only available crystal structure complex of calreticulin with a tetrasaccharide (Glc1Man3) shows interesting features. First, the rings of the gentamicin occupy the positions of glucose and the first two mannose sugars of the tetrasaccharide molecule. Second, the oxygen atoms of the glycosidic linkage of these two ligands have a positional deviation of 1.3 Ǻ. The predicted binding constant of 16.9 μM is in accordance with the previous kinetic study experiments. The details therefore, strongly implicate gentamicin as a competitive inhibitor of sugar binding with calreticulin.

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Abbreviations

ABNR:

Adopted basis set Newton-Raphson

CHARMM:

Chemistry at Harvard molecular mechanics

PROCHECK:

Protein structure check

PDB:

Protein Data Bank

r.m.s:

root mean square

MMFF:

Merck molecular force field

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Acknowledgments

The ‘Pool Officer fellowship’ to GH from the Council of Scientific and Industrial Research is acknowledged. The financial support given to the Biomedical Informatics Center at the institute by the Indian Council of Medical Research, Government of India, is gratefully acknowledged.

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Authors and Affiliations

  1. Department of Biophysics, All India Institute of Medical Sciences, 110029, New Delhi, India

    Gururao Hariprasad, Manoj Kumar, Komal Rani, Punit Kaur & Alagiri Srinivasan

Authors
  1. Gururao Hariprasad
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  2. Manoj Kumar
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  3. Komal Rani
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  4. Punit Kaur
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  5. Alagiri Srinivasan
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Corresponding author

Correspondence to Alagiri Srinivasan.

Additional information

Gururao Hariprasad and Manoj Kumar have contributed equally in the paper

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Fig. SI

Sequence homology studies of calreticulin from different species within the mammalian group. Amino acid numbers are given at the end of every sequence block. The mouse calreticulin sequence whose structure is considered for the docking studies is shown in green. % identity and sequence accession numbers are given at the end of the respective sequences. The sequences are of mouse, Mus muscullus (Mm); rat, Rattus norvegius (Rn), rabbit, Oryctolagus cuniculus (Oc), human, Homo sapiens (Hs); pig, Sus scrofa (Ss) and cow, Bos taurus (Bt). ‘*’ are marked for identical residues, ‘:’ are marked for conserved residues and ‘.’ are marked for semi-conserved residues. The conserved cysteines are shown in yellow and the residues making interactions with the sugar in the crystal structure complex (PDB ID: 3O0W) are shown in bold. The residues that have been removed from the protein are shown in gray. A few dashes are introduced to enhance similarities. (JPEG 291 kb)

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Hariprasad, G., Kumar, M., Rani, K. et al. Aminoglycoside induced nephrotoxicity: molecular modeling studies of calreticulin-gentamicin complex. J Mol Model 18, 2645–2652 (2012). https://doi.org/10.1007/s00894-011-1289-8

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  • DOI: https://doi.org/10.1007/s00894-011-1289-8

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