1AZ5

UNLIGANDED SIV PROTEASE STRUCTURE IN AN "OPEN" CONFORMATION

Summary for 1AZ5

• Entry DOI: 10.2210/pdb1az5/pdb
• Descriptor: SIV PROTEASE (2 entities in total)
• Functional Keywords: hiv, aids, proteinase, aspartyl protease, endonuclease
• Biological source: Simian immunodeficiency virus
• Cellular location: Matrix protein p17: Virion (Potential). Capsid protein p24: Virion (Potential). Nucleocapsid protein p7: Virion (Potential). Reverse transcriptase/ribonuclease H: Virion (Potential). Integrase: Virion (Potential): P05896
• Total number of polymer chains: 1
• Total formula weight: 10768.43

Authors

Rose, R.B.,Craik, C.S.,Stroud, R.M. (deposition date: 1997-11-25, release date: 1998-05-27, Last modification date: 2024-04-03)

Primary citation

Rose, R.B.,Craik, C.S.,Stroud, R.M.
Domain flexibility in retroviral proteases: structural implications for drug resistant mutations.
Biochemistry, 37:2607-2621, 1998

PubMed Abstract: 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.

PubMed: 9485411
DOI: 10.1021/bi9716074

Experimental method

X-RAY DIFFRACTION (2 Å)