Structural basis of drug resistance by genetic variants of HIV type 1 clade C protease from India

Abraham Kandathil, Agnel Praveen Joseph, Rajesh Kannangai, Narayanaswamy Srinivasan, Oriapadickal Cherian Abraham, Susanne Alexander Pulimood, Gopalan Sridharan

Research output: Contribution to journalArticle

Abstract

Using computer modeling of three-dimensional structures and structural information available on the crystal structures of HIV-1 protease, we investigated the structural effects of mutations, in treatment-naive and treatment-exposed individuals from India and postulated mechanisms of resistance in clade C variants. A large number of models (14) have been generated by computational mutation of the available crystal structures of drug bound proteases. Localized energy minimization was carried out in and around the sites of mutation in order to optimize the geometry of interactions present. Most of the mutations result in structural differences at the flap that favors the semiopen state of the enzyme. Some of the mutations were also found to confer resistance by affecting the geometry of the active site. The E35D mutation affects the flap structure in clade B strains and E35N and E35K mutation, seen in our modeled strains, have a more profound effect. Common polymorphisms at positions 36 and 63 in clade C also affected flap structure. Apart from a few other residues Gln-58, Asn-83, Asn-88, and Gln-92 and their interactions are important for the transition from the closed to the open state. Development of protease inhibitors by structure-based design requires investigation of mechanisms operative for clade C to improve the efficacy of therapy.

Original languageEnglish (US)
Pages (from-to)511-519
Number of pages9
JournalAIDS Research and Human Retroviruses
Volume25
Issue number5
DOIs
StatePublished - May 1 2009
Externally publishedYes

Fingerprint

Drug Resistance
HIV-1
India
Mutation
protease C
Protease Inhibitors
Catalytic Domain
Peptide Hydrolases
Enzymes
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Cite this

Kandathil, A., Joseph, A. P., Kannangai, R., Srinivasan, N., Abraham, O. C., Pulimood, S. A., & Sridharan, G. (2009). Structural basis of drug resistance by genetic variants of HIV type 1 clade C protease from India. AIDS Research and Human Retroviruses, 25(5), 511-519. https://doi.org/10.1089/aid.2008.0102

Structural basis of drug resistance by genetic variants of HIV type 1 clade C protease from India. / Kandathil, Abraham; Joseph, Agnel Praveen; Kannangai, Rajesh; Srinivasan, Narayanaswamy; Abraham, Oriapadickal Cherian; Pulimood, Susanne Alexander; Sridharan, Gopalan.

In: AIDS Research and Human Retroviruses, Vol. 25, No. 5, 01.05.2009, p. 511-519.

Research output: Contribution to journalArticle

Kandathil, A, Joseph, AP, Kannangai, R, Srinivasan, N, Abraham, OC, Pulimood, SA & Sridharan, G 2009, 'Structural basis of drug resistance by genetic variants of HIV type 1 clade C protease from India', AIDS Research and Human Retroviruses, vol. 25, no. 5, pp. 511-519. https://doi.org/10.1089/aid.2008.0102
Kandathil, Abraham ; Joseph, Agnel Praveen ; Kannangai, Rajesh ; Srinivasan, Narayanaswamy ; Abraham, Oriapadickal Cherian ; Pulimood, Susanne Alexander ; Sridharan, Gopalan. / Structural basis of drug resistance by genetic variants of HIV type 1 clade C protease from India. In: AIDS Research and Human Retroviruses. 2009 ; Vol. 25, No. 5. pp. 511-519.
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