Similarities in the HIV-1 and ASV integrase active sites upon metal cofactor binding

Lins, Roberto D.; Straatsma, T. P.; Briggs, James M.

doi:10.1002/(sici)1097-0282(20000405)53:4<308::aid-bip3>3.0.co;2-h

Cited by 27 publications

(17 citation statements)

References 43 publications

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“…The mapping of the electrostatic potential onto (or near) the molecular surface has been widely used in biomolecular simulations since it is particularly useful in the understanding of molecular interactions. [31][32][33][34] Formally, the electrostatic potential has contributions from the n nuclei and the electrons represented by the electron density . It can be written as:…”

Section: -29mentioning

confidence: 99%

Influence of the B-band O-antigen chain in the structure and electrostatics of the lipopolysaccharide membrane of Pseudomonas aeruginosa

Soares¹,

Straatsma²,

Lins³

2008

J. Braz. Chem. Soc.

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Lipopolissacarídeos são os principais constituintes da membrana externa de bactérias Gramnegativas. Esta classe de compostos desempenha um papel fundamental em processos químicos mediados por estas bactérias como o reconhecimento e ligação de metais, adesão a superfícies e reações de óxido-redução. Lipopolissacarídeos são também os mais comuns agentes causadores de doenças nosocomiais que levam a infecções crônicas e agudas em pacientes de queimaduras, deficiência imunológica e fibrose cística. Variação fenotípica na expressão de bandas A e B em membranas lipopolissacarídicas de P. aeruginosa resultam em mudanças de propriedades químicas da superfície bacteriana que afetam a adesão bacteriana a superfícies celulares e favorecem a sobrevivência do organismo. Simulações de dinâmica molecular clássica em solvente explícito foram realizadas para a membrana lipopolissacarídica lisa (A-B+ LPS) de Pseudomonas aeruginosa por um período de 12 ns. A banda B exibe uma grande flexibilidade e permanece solvatada durante o período de simulação. Interações de longo alcance entre a banda B e as moléculas de carboidratos na superfície da membrana não foram observadas corroborando resultados postulados anteriormente através de experimentos de microscopia de forca atômica. Comparações com simulações da membrana lipopolissacarídica rugosa (A-B-LPS) de P. aeruginosa indicam que a presença da banda B induz uma expansão da membrana e modifica drasticamente tanto o potencial eletrostático através da membrana como a distribuição de cargas na superfície da mesma. Estes resultados oferecem uma explicação para o fato de que apenas as cepas de P. aeruginosa que contem a banda B são capazes de se aderirem a superfícies celulares, e para a necessidade de perda da banda B para que então estes organismos possam iniciar uma infecção aguda em adição à infecção crônica do paciente.Lipopolysaccharides (LPSs) form the major constituent of the outer membrane of Gram-negative bacteria, and are believed to play a key role in processes that govern microbial metal binding, surface adhesion, and microbe-mediated oxidation/reduction reactions. It is also a major causative agent of nosocomial illness, eliciting both chronic and acute infections in burn, immunocompromised, and cystic fibrosis. Phenotypic variation in the relative expression of A-and B-band in the LPS of Pseudomonas aeruginosa seems to alter its overall surface characteristics influencing adhesion and favoring survival. Classical molecular dynamics simulations of A-B+ LPS membrane model of P. aeruginosa were carried out in explicit solvent for 12+ ns. The B-band presents a remarkable flexibility remaining fully solvated and does not interact with the sugar units from the LPS core surface residues, in agreement with atomic force microscopy experiments. Comparison with previous simulations of the rough LPS membrane suggests that the presence of the B-band promotes membrane expansion. In addition, this O-antigen chain dramatically alters the electrostatic potential and surface charge of the LPS ...

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Section: -29mentioning

confidence: 99%

Influence of the B-band O-antigen chain in the structure and electrostatics of the lipopolysaccharide membrane of Pseudomonas aeruginosa

Soares¹,

Straatsma²,

Lins³

2008

J. Braz. Chem. Soc.

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“…The largest (amino acids 50 -207 in ASV IN) is the central catalytic core domain (CCD or "core"). This domain contains the DD(35)E motif of acidic residues that coordinate the required divalent metal ions, Mg 2ϩ or Mn 2ϩ (3)(4)(5)(6). The isolated HIV IN core domain forms a dimer in solution (7), and the three-dimensional structure of the core from several retroviral IN proteins has been solved by x-ray crystallography of either the isolated domain or two-domain fragments that include the N-(NTD) or C-terminal (CTD) domains (8 -14).…”

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confidence: 99%

Architecture of a Full-length Retroviral Integrase Monomer and Dimer, Revealed by Small Angle X-ray Scattering and Chemical Cross-linking

Bojja

Andrake

Weigand

et al. 2011

Journal of Biological Chemistry

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We determined the size and shape of full-length avian sarcoma virus (ASV) integrase (IN) monomers and dimers in solution using small angle x-ray scattering. The low resolution data obtained establish constraints for the relative arrangements of the three component domains in both forms. Domain organization within the small angle x-ray envelopes was determined by combining available atomic resolution data for individual domains with results from cross-linking coupled with mass spectrometry. The full-length dimer architecture so revealed is unequivocally different from that proposed from x-ray crystallographic analyses of two-domain fragments, in which interactions between the catalytic core domains play a prominent role. Core-core interactions are detected only in cross-linked IN tetramers and are required for concerted integration. The solution dimer is stabilized by C-terminal domain (CTD-CTD) interactions and by interactions of the N-terminal domain in one subunit with the core and CTD in the second subunit. These results suggest a pathway for formation of functional IN-DNA complexes that has not previously been considered and possible strategies for preventing such assembly. Retroviral integrase (IN)3 catalyzes the insertion of viral DNA into the DNA of the infected host cell. IN is one of three retrovirally encoded enzymes that are essential for retroviral replication and therefore is an important target for drugs to treat HIV/AIDS. One IN active site-directed inhibitor, raltegravir, is approved by the Food and Drug Administration for this purpose, and a second, elvitegravir, is in advanced clinical trials.

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“…Structural studies of IN revealed a single binding site for Mg 2ϩ and Mn 2ϩ (20,35), while two Cd 2ϩ or Zn 2ϩ ions separated by 3.6 to 3.7 Å were observed (4,5,49). Indeed, it is believed that a second Mg 2ϩ ion is carried into the integrase active site by the substrate (31).…”

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Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase, RNase H, and Integrase Activities by Hydroxytropolones

Didierjean¹,

Isel²,

Querré

et al. 2005

Antimicrob Agents Chemother

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Human immunodeficiency virus type I reverse transcriptase (RT) possesses distinct DNA polymerase and RNase H sites, whereas integrase (IN) uses the same active site to perform 3-end processing and strand transfer of the proviral DNA. These four enzymatic activities are essential for viral replication and require metal ions. Two Mg 2؉ ions are present in the RT polymerase site, and one or two Mg 2؉ ions are required for the catalytic activities of RNase H and IN. We tested the possibility of inhibition of the RT polymerase and RNase H as well as the IN 3-end processing and transfer activities of purified enzymes by a series of 3,7-dihydroxytropolones designed to target two Mg 2؉ ions separated by ϳ3.7 Å. The RT polymerase and IN 3 processing and strand transfer activities were inhibited at submicromolar concentrations, while the RNase H activity was inhibited in the low micromolar range. In all cases, the lack of inhibition by tropolones and O-methylated 3,7-dihydroxytropolones was consistent with the active molecules binding the metal ions in the active site. In addition, inhibition of the DNA polymerase activity was shown to depend on the Mg 2؉ concentration. Furthermore, selective inhibitors were identified for several of the activities tested, leaving some potential for design of improved inhibitors. However, all tested compounds exhibited cellular toxicity that presently limits their applications.

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Similarities in the HIV-1 and ASV integrase active sites upon metal cofactor binding

Cited by 27 publications

References 43 publications

Influence of the B-band O-antigen chain in the structure and electrostatics of the lipopolysaccharide membrane of Pseudomonas aeruginosa

Influence of the B-band O-antigen chain in the structure and electrostatics of the lipopolysaccharide membrane of Pseudomonas aeruginosa

Architecture of a Full-length Retroviral Integrase Monomer and Dimer, Revealed by Small Angle X-ray Scattering and Chemical Cross-linking

Inhibition of Human Immunodeficiency Virus Type 1 Reverse Transcriptase, RNase H, and Integrase Activities by Hydroxytropolones

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