Flaps Morph for HIV Protease: Difference between revisions
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<StructureSection load='' size='350' side='right' caption='HIV protease: morph of flaps opening/closing ([[1hxw]] ↔ [[1tw7]]' scene=''> | <StructureSection load='' size='350' side='right' caption='HIV protease: morph of flaps opening/closing ([[1hxw]] ↔ [[1tw7]]' scene='83/836583/Morph/1'> | ||
The genome of HIV codes for synthesis of a polyprotein (UniProt [https://www.uniprot.org/uniprot/P04585 P04585 (POL_HV1H2)]) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation<ref name="wide-open">PMID:16338417</ref>. Drugs that inhibit HIV protease prevent the virus from replicating, and are [[Molecular Playground/HIV Protease Inhibitor|crucial components of anti-HIV therapies]]. | The genome of HIV codes for synthesis of a polyprotein (UniProt [https://www.uniprot.org/uniprot/P04585 P04585 (POL_HV1H2)]) that requires cutting by HIV protease in order to be separated into individual mature proteins required for virus maturation<ref name="wide-open">PMID:16338417</ref>. Drugs that inhibit HIV protease prevent the virus from replicating, and are [[Molecular Playground/HIV Protease Inhibitor|crucial components of anti-HIV therapies]]. | ||
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There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have nearly always been closed<ref name="processes">Yu, Y. ''et al.'', Structural insights into HIV-1 protease flap opening processes and key intermediates. 2017 RSC Advances, '''7''':45121-8. '''NOT IN PUBMED.''' [https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra09691g OPEN ACCESS]. DOI: [https://doi.org/10.1039/C7RA09691G 10.1039/C7RA09691G].</ref>. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. As of 2017, no crystal structure has captured a '''fully open''' conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps<ref name="wide-open" />. | There are [[Immunodeficiency virus protease 3D structures|hundreds of HIV protease crystal structures]]. When crystallized with bound inhibitor, the flaps have nearly always been closed<ref name="processes">Yu, Y. ''et al.'', Structural insights into HIV-1 protease flap opening processes and key intermediates. 2017 RSC Advances, '''7''':45121-8. '''NOT IN PUBMED.''' [https://pubs.rsc.org/en/content/articlehtml/2017/ra/c7ra09691g OPEN ACCESS]. DOI: [https://doi.org/10.1039/C7RA09691G 10.1039/C7RA09691G].</ref>. Inhibitor-free crystal structures have been classified into '''closed, semi-open,''' and '''wide open'''<ref name="processes" />. As of 2017, no crystal structure has captured a '''fully open''' conformation, defined as a distance of >13 Å between isoleucine 50's at the tips of the flaps<ref name="wide-open" />. | ||
Here is shown a morph between a closed HIV protease and a "wide open" protease. (Note that "wide open" is not "fully open" -- see above.) | Here is shown a morph between a closed HIV protease and a "wide open" protease (<scene name='83/836583/Morph/1'>restore initial scene</scene>). (Note that "wide open" is not "fully open" -- see above.) | ||
In the case of mutant [[1tw7]], about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | In the case of mutant [[1tw7]], about 100 water molecules reside in the active site, forming a hydrogen-bonded scaffold holding the flaps open<ref name="wide-open" />. | ||