1az5
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Rigid body rotation of five domains and movements within their interfacial, joints provide a rational context for understanding why HIV protease, mutations that arise in drug resistant strains are often spatially removed, from the drug or substrate binding sites. Domain motions associated with, substrate binding in the retroviral HIV-1 and SIV proteases are identified, and characterized. These motions are in addition to closure of the flaps, and result from rotations of approximately 6-7 degrees at primarily, hydrophobic interfaces. A crystal structure of unliganded SIV protease, (incorporating the point mutation Ser 4 His to stabilize the protease, against autolysis) was determined to 2.0 A resolution in a new space, group, P3221. The structure is in the most "open" conformation of any, ... | + | Rigid body rotation of five domains and movements within their interfacial, joints provide a rational context for understanding why HIV protease, mutations that arise in drug resistant strains are often spatially removed, from the drug or substrate binding sites. Domain motions associated with, substrate binding in the retroviral HIV-1 and SIV proteases are identified, and characterized. These motions are in addition to closure of the flaps, and result from rotations of approximately 6-7 degrees at primarily, hydrophobic interfaces. A crystal structure of unliganded SIV protease, (incorporating the point mutation Ser 4 His to stabilize the protease, against autolysis) was determined to 2.0 A resolution in a new space, group, P3221. The structure is in the most "open" conformation of any, retroviral protease so far examined, with six residues of the flaps, disordered. Comparison of this and unliganded HIV structures, with their, respective liganded structures by difference distance matrixes identifies, five domains of the protease dimer that move as rigid bodies against one, another: one terminal domain encompassing the N- and C-terminal beta sheet, of the dimer, two core domains containing the catalytic aspartic acids, and two flap domains. The two core domains rotate toward each other on, substrate binding, reshaping the binding pocket. We therefore show that, for enzymes, mutations at interdomain interfaces that favor the unliganded, form of the target active site will increase the off-rate of the, inhibitor, allowing the substrate greater access for catalysis. This, offers a mechanism of resistance to competitive inhibitors, especially, when the forward enzymatic reaction rate exceeds the rate of substrate, dissociation. |
==About this Structure== | ==About this Structure== | ||
| - | 1AZ5 is a | + | 1AZ5 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Simian_immunodeficiency_virus Simian immunodeficiency virus]. Active as [http://en.wikipedia.org/wiki/HIV-1_retropepsin HIV-1 retropepsin], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.23.16 3.4.23.16] Structure known Active Site: NUL. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1AZ5 OCA]. |
==Reference== | ==Reference== | ||
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[[Category: proteinase]] | [[Category: proteinase]] | ||
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 5 15:12:49 2007'' |
Revision as of 13:07, 5 November 2007
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UNLIGANDED SIV PROTEASE STRUCTURE IN AN "OPEN" CONFORMATION
Overview
Rigid body rotation of five domains and movements within their interfacial, joints provide a rational context for understanding why HIV protease, mutations that arise in drug resistant strains are often spatially removed, from the drug or substrate binding sites. Domain motions associated with, substrate binding in the retroviral HIV-1 and SIV proteases are identified, and characterized. These motions are in addition to closure of the flaps, and result from rotations of approximately 6-7 degrees at primarily, hydrophobic interfaces. A crystal structure of unliganded SIV protease, (incorporating the point mutation Ser 4 His to stabilize the protease, against autolysis) was determined to 2.0 A resolution in a new space, group, P3221. The structure is in the most "open" conformation of any, retroviral protease so far examined, with six residues of the flaps, disordered. Comparison of this and unliganded HIV structures, with their, respective liganded structures by difference distance matrixes identifies, five domains of the protease dimer that move as rigid bodies against one, another: one terminal domain encompassing the N- and C-terminal beta sheet, of the dimer, two core domains containing the catalytic aspartic acids, and two flap domains. The two core domains rotate toward each other on, substrate binding, reshaping the binding pocket. We therefore show that, for enzymes, mutations at interdomain interfaces that favor the unliganded, form of the target active site will increase the off-rate of the, inhibitor, allowing the substrate greater access for catalysis. This, offers a mechanism of resistance to competitive inhibitors, especially, when the forward enzymatic reaction rate exceeds the rate of substrate, dissociation.
About this Structure
1AZ5 is a Single protein structure of sequence from Simian immunodeficiency virus. Active as HIV-1 retropepsin, with EC number 3.4.23.16 Structure known Active Site: NUL. Full crystallographic information is available from OCA.
Reference
Domain flexibility in retroviral proteases: structural implications for drug resistant mutations., Rose RB, Craik CS, Stroud RM, Biochemistry. 1998 Feb 24;37(8):2607-21. PMID:9485411
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