Flaps Morph for HIV Protease: Difference between revisions
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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" />. 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" />. Drugs that inhibit HIV protease prevent the virus from replicating, and are [[Molecular Playground/HIV Protease Inhibitor|crucial components of anti-HIV therapies]]. | ||
The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|covered by two "flaps"]]. It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<ref name="wide-open" />. | The proteolytic active site of HIV protease is [[Immunodeficiency virus protease|covered by two "flaps"]]. It is believed that these flaps must open to enable substrate polyprotein to enter the active site. Drugs that inhibit HIV protease tend to "lock" the flaps closed<ref>PMID:22291339</ref>. Mutations in HIV protease that confer resistance to inhibitor drugs often involve changes to the flaps<ref name="wide-open" />. The ''active site expansion'' hypothesis states that mutations responsible for multi-drug resistance expand the active site cavity, thereby reducing drug affinity<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 always been closed<ref name="processes" />. 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 always been closed<ref name="processes" />. 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" />. | ||
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*Course-grained<ref>PMID:17029846 </ref> | *Course-grained<ref>PMID:17029846 </ref> | ||
*2017: '''HAVE PDF'''<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> | *2017: '''HAVE PDF'''<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> | ||