Sandbox Reserved 958: Difference between revisions
No edit summary |
No edit summary |
||
| Line 50: | Line 50: | ||
Recent advances allow the discovery of a new inhibitor class which acts in a dissimilar way from that of INSTIs. These compounds exert their inhibitory effect by binding to a highy conserved allosteric pocket on the catalytic core domain dimer ('''CCD-CCD dimer''') mediated through the alpha helice 1 and 5<ref name="Engelman">PMID:23647983</ref>. | Recent advances allow the discovery of a new inhibitor class which acts in a dissimilar way from that of INSTIs. These compounds exert their inhibitory effect by binding to a highy conserved allosteric pocket on the catalytic core domain dimer ('''CCD-CCD dimer''') mediated through the alpha helice 1 and 5<ref name="Engelman">PMID:23647983</ref>. | ||
In a normal HIV-1 life cycle, the cellular co-factor LEDGF/p75 engages the enzyme at the CCD-CCD dimer via its '''I'''ntegrase '''B'''inding '''D'''omain ('''IBD'''). By binding this allosteric pocket, LEDGF/p75 stimulates both concerted integration and strand transfer. It has also be shown that LEDGF-integrase complex exhibits a better solubility profiles compared to the free integrase. This co-factor increases the tetrameric stability of integrase in order to tether the integration to active genes<ref name="Dells">PMID: 19091057</ref>. | In a normal HIV-1 life cycle, the cellular co-factor LEDGF/p75 engages the enzyme at the CCD-CCD dimer via its '''I'''ntegrase '''B'''inding '''D'''omain ('''IBD'''). By binding this allosteric pocket, LEDGF/p75 stimulates both concerted integration and strand transfer. It has also be shown that LEDGF-integrase complex exhibits a better solubility profiles compared to the free integrase. This co-factor increases the tetrameric stability of integrase in order to tether the integration to active genes<ref name="Dells">PMID: 19091057</ref>. | ||
LEDGF/p75 contacts on one integrase subunit via hydrogen bonds between the cofactor residue '''Asp366''' and the primary amino groups of integrase residues <scene name='60/604477/Glu170_his171/1'>Glu170 and His171</scene>. LEDGF/p75 residue '''Ile365''' contacts on the other integrase subunit by nesting into a hydrophobic pocket which consists of residues <scene name='60/604477/ | LEDGF/p75 contacts on one integrase subunit via hydrogen bonds between the cofactor residue '''Asp366''' and the primary amino groups of integrase residues <scene name='60/604477/Glu170_his171/1'>Glu170 and His171</scene>. LEDGF/p75 residue '''Ile365''' contacts on the other integrase subunit by nesting into a hydrophobic pocket which consists of residues <scene name='60/604477/Leu_ala_trp_residues2/1'>Leu102, Ala128 and Trp132</scene><ref name="Engelman">PMID:23647983</ref>. | ||
This new class of inhibitor, by engaging this allosteric pocket, prevents the binding of LEDGF/p75 and inhibits the integrase activity by enhancing the formation of integrase multimers, which impedes the intasome assembly<ref name="Engelman">PMID:23647983</ref>. | This new class of inhibitor, by engaging this allosteric pocket, prevents the binding of LEDGF/p75 and inhibits the integrase activity by enhancing the formation of integrase multimers, which impedes the intasome assembly<ref name="Engelman">PMID:23647983</ref>. | ||