1dif
From Proteopedia
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|PDB= 1dif |SIZE=350|CAPTION= <scene name='initialview01'>1dif</scene>, resolution 1.70Å | |PDB= 1dif |SIZE=350|CAPTION= <scene name='initialview01'>1dif</scene>, resolution 1.70Å | ||
|SITE= | |SITE= | ||
| - | |LIGAND= | + | |LIGAND= <scene name='pdbligand=A85:N-{1-BENZYL-2,2-DIFLUORO-3,3-DIHYDROXY-4-[3-METHYL-2-(3-METHYL-3-PYRIDIN-2-YLMETHYL-UREIDO)-BUTYRYLAMINO]-5-PHENYL-PENTYL}-3-METHYL-2-(3-METHYL-3-PYRIDIN-2-YLMETHYL-UREIDO)-BUTYRAMIDE'>A85</scene>, <scene name='pdbligand=BME:BETA-MERCAPTOETHANOL'>BME</scene> |
|ACTIVITY= | |ACTIVITY= | ||
|GENE= | |GENE= | ||
| + | |DOMAIN= | ||
| + | |RELATEDENTRY= | ||
| + | |RESOURCES=<span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1dif FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1dif OCA], [http://www.ebi.ac.uk/pdbsum/1dif PDBsum], [http://www.rcsb.org/pdb/explore.do?structureId=1dif RCSB]</span> | ||
}} | }} | ||
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[[Category: Sham, H L.]] | [[Category: Sham, H L.]] | ||
[[Category: Silva, A M.]] | [[Category: Silva, A M.]] | ||
| - | [[Category: A85]] | ||
| - | [[Category: BME]] | ||
[[Category: aspartic proteinase]] | [[Category: aspartic proteinase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun Mar 30 19:42:06 2008'' |
Revision as of 16:42, 30 March 2008
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| , resolution 1.70Å | |||||||
|---|---|---|---|---|---|---|---|
| Ligands: | , | ||||||
| Resources: | FirstGlance, OCA, PDBsum, RCSB | ||||||
| Coordinates: | save as pdb, mmCIF, xml | ||||||
HIV-1 PROTEASE IN COMPLEX WITH A DIFLUOROKETONE CONTAINING INHIBITOR A79285
Overview
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.
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
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