Alternative Native Flap Conformation Revealed by 2·3 Å Resolution Structure of SIV Proteinase

Authors: Wilderspin A.F.; Sugrue R.J.

Source: Journal of Molecular Biology, Volume 239, Number 1, May 1994 , pp. 97-103(7)

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Abstract:

A large conformational change is observed between HIV-1 proteinase in the ligand-free state and in complexes with transition-state inhibitors. Crystal structures of this enzyme have either the flaps open for the native or ligand-free enzyme or the flaps closed for peptidomimetic ligand-bond enzyme. We describe the structure of native recombinant SIV proteinase which like other retroviral proteinases crytallizes as a perfect 2-fold symmetric dimer but in a different crystal packing arrangement. In contrast to HIV-1 PR we show that SIV proteinase in the ligand-free state adopts the closed flaps conformation, demonstrating that binding is not a prerequisite for the closed flaps conformation. The catalytic water was clearly observed between the two aspartates which were not perfectly co-planar, and in this structure the active site cleft is more restricted than for either inhibitor bound or ligand-free HIV-1 proteinase. Accommodation of two bulkier side-chains in the simian enzyme core has resulted in a more exposed N terminus than for HIV-1 PR which we predict could enhance autocatalytic cleavage at the N terminus.Copyright 1994, 1999 Academic Press

Keywords: SIV proteinase; flap conformation; retroviral proteinase; AIDS; X-ray structure

Language: English

Document Type: Research article

DOI: http://dx.doi.org/10.1006/jmbi.1994.1353

Affiliations: Laboratory of Molecular Biology, Department of Crystallography Birkbeck College, Malet Street, London WC1E 7HX, England

Publication date: 1994-05-01