1az5
From Proteopedia
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==Overview== | ==Overview== | ||
| - | Rigid body rotation of five domains and movements within their interfacial | + | 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== | ||
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[[Category: Simian immunodeficiency virus]] | [[Category: Simian immunodeficiency virus]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
| - | [[Category: Craik, C | + | [[Category: Craik, C S.]] |
| - | [[Category: Rose, R | + | [[Category: Rose, R B.]] |
| - | [[Category: Stroud, R | + | [[Category: Stroud, R M.]] |
[[Category: aids]] | [[Category: aids]] | ||
[[Category: aspartyl protease]] | [[Category: aspartyl protease]] | ||
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[[Category: proteinase]] | [[Category: proteinase]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 11:49:46 2008'' |
Revision as of 09:49, 21 February 2008
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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 Known structural/functional Site: . 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
Page seeded by OCA on Thu Feb 21 11:49:46 2008
