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| | {{STRUCTURE_1dif| PDB=1dif | SCENE= }} | | {{STRUCTURE_1dif| PDB=1dif | SCENE= }} |
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| - | '''HIV-1 PROTEASE IN COMPLEX WITH A DIFLUOROKETONE CONTAINING INHIBITOR A79285'''
| + | ===HIV-1 PROTEASE IN COMPLEX WITH A DIFLUOROKETONE CONTAINING INHIBITOR A79285=== |
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| - | ==Overview==
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| - | The structure of the HIV-1 protease in complex with a pseudo-C2 symmetric inhibitor, which contains a central difluoroketone motif, has been determined with X-ray diffraction data extending to 1.7 A resolution. The electron density map clearly indicates that the inhibitor is bound in a symmetric fashion as the hydrated, or gemdiol, form of the difluoroketone. Refinement of the complex reveals a unique, and almost symmetric, set of interactions between the geminal hydroxyl groups, the geminal fluorine atoms, and the active-site aspartate residues. Several hydrogen bonding patterns are consistent with that conformation. The lowest energy hydrogen disposition, as determined by semiempirical energy calculations, shows only one active site aspartate protonated. A comparison between the corresponding dihedral angles of the difluorodiol core and those of a hydrated peptide bond analog, calculated ab-initio, shows that the inhibitor core is a mimic of a hydrated peptide bond in a gauche conformation. The feasibility of an anti-gauche transition for a peptide bond after hydration is verified by extensive molecular dynamics simulations. The simulations suggest that rotation about the C-N scissile bond would readily occur after hydration and would be driven by the optimization of the interactions of peptide side-chains with the enzyme. These results, together with the characterization of a transition state leading to bond breakage via a concerted exchange of two protons, suggest a proteolysis mechanism whereby only one active site aspartate is initially protonated. The steps of this mechanism are: asymmetric binding of the substrate; hydration of the peptidic carbonyl by an active site water; proton translocation between the active site aspartate residues simultaneously with carbonyl hydration; optimization of the binding of the entire substrate facilitated by the flexible structure of the hydrated peptide bond, which, in turn, forces the hydrated peptide bond to assume a gauche conformation; simultaneous proton exchange whereby one hydroxyl donates a proton to the charged aspartate, and, at the same time, the nitrogen lone pair accepts a proton from the other aspartate; and, bond breakage and regeneration of the initial protonation state of the aspartate residues. | + | The line below this paragraph, {{ABSTRACT_PUBMED_8551523}}, adds the Publication Abstract to the page |
| | + | (as it appears on PubMed at http://www.pubmed.gov), where 8551523 is the PubMed ID number. |
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| | + | {{ABSTRACT_PUBMED_8551523}} |
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| | ==About this Structure== | | ==About this Structure== |
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| | [[Category: Silva, A M.]] | | [[Category: Silva, A M.]] |
| | [[Category: Aspartic proteinase]] | | [[Category: Aspartic proteinase]] |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri May 2 13:52:51 2008'' | + | |
| | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Jun 30 23:06:37 2008'' |
Revision as of 20:06, 30 June 2008
Template:STRUCTURE 1dif
HIV-1 PROTEASE IN COMPLEX WITH A DIFLUOROKETONE CONTAINING INHIBITOR A79285
Template:ABSTRACT PUBMED 8551523
About this Structure
1DIF is a Single protein structure of sequence from Human immunodeficiency virus 1. Full crystallographic information is available from OCA.
Reference
Inhibition and catalytic mechanism of HIV-1 aspartic protease., Silva AM, Cachau RE, Sham HL, Erickson JW, J Mol Biol. 1996 Jan 19;255(2):321-46. PMID:8551523
Page seeded by OCA on Mon Jun 30 23:06:37 2008
