3tl9 | pdb_00003tl9

crystal structure of HIV protease model precursor/Saquinavir complex

spinqualitylabelsall models 3tl9, resolution 1.32Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3tl9 is a 2 chain structure with sequence from Human immunodeficiency virus type 1 (bru isolate). Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: CL, GOL, NA, ROC Gene: gag-pol (Human immunodeficiency virus type 1 (BRU ISOLATE)) Activity: HIV-1 retropepsin, with EC number 3.4.23.16 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed The HIV-1 protease (PR) mediates its own release (autoprocessing) from the polyprotein precursor, Gag-Pol, flanked by the transframe region (TFR) and reverse transcriptase at its N- and C-termini, respectively. Autoprocessing at the N-terminus of PR mediates stable dimer formation essential for catalytic activity, leading to the formation of infectious virus. An antiparallel beta-sheet interface formed by the four N- and C-terminal residues of each subunit is important for dimer stability. Here, we present the first high-resolution crystal structures of model protease precursor-clinical inhibitor (PI darunavir or saquinavir) complexes, revealing varying conformations of the N-terminal flanking (S(-4)FNF(-1)) and interface residues (P(1)QIT(4)). A 180 degrees rotation of the T(4)-L(5) peptide bond is accompanied by a new Q(2)-L(5) hydrogen bond and complete disengagement of PQIT from the beta-sheet dimer interface, which may be a feature for intramolecular autoprocessing. This result is consistent with drastically lower thermal stability by 14-20 degrees C of PI complexes of precursors and the mature PR lacking its PQIT residues (by 18.3 degrees C). Similar to the TFR-PR precursor, this deletion also results in a darunavir dissociation constant (2 x 10(4))-fold higher and a markedly increased dimer dissociation constant relative to the mature PR. The terminal beta-sheet perturbations of the dimeric structure likely account for the drastically poorer inhibition of autoprocessing of TFR-PR relative to the mature PR, even though significant differences in active site-PI interactions in these structures were not observed. The novel conformations of the dimer interface may be exploited to target selectively the protease precursor prior to its N-terminal cleavage. Terminal interface conformations modulate dimer stability prior to amino terminal autoprocessing of HIV-1 protease.,Agniswamy J, Sayer JM, Weber IT, Louis JM Biochemistry. 2012 Feb 7;51(5):1041-50. Epub 2012 Jan 24. PMID:22242794 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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