Abstract
The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We propose an exhaustive study of the local structural asymmetry between the two monomers of all available PR2 structures complexed with various inhibitors using a structural alphabet approach. On average, PR2 exhibits asymmetry in 31% of its positions—i.e., exhibiting different backbone local conformations in the two monomers. This asymmetry was observed all along its structure, particularly in the elbow and flap regions. We first differentiated structural asymmetry conserved in most PR2 structures from the one specific to some PR2. Then, we explored the origin of the detected asymmetry in PR2. We localized asymmetry that could be induced by PR2’s flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. This latter could be important for the PR2’s adaptation to diverse ligands. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity. This knowledge is critical for a better description of PR2’s recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class.
Highlights
The human immunodeficiency virus (HIV)-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands
It is the first time that the structural asymmetry of the α-helix of PR2 is highlighted. From these structural asymmetric positions, we differentiated overrepresented asymmetric positions (28%), which are characterized by structural asymmetry of high magnitude, from the asymmetric positions with a low frequency (72%)
We suggest that this asymmetry, especially at position 40, is important for structural changes of PR2 and for the transition from semi-open to closed conformations
Summary
The HIV-2 protease (PR2) is a homodimer of 99 residues with asymmetric assembly and binding various ligands. We localized asymmetry that could be induced by PR2’s flexibility, allowing transition from the semi-open to closed conformations and the asymmetry potentially induced by ligand binding. Our results highlighted some differences between asymmetry of PR2 bound to darunavir and amprenavir that could explain their differences of affinity This knowledge is critical for a better description of PR2’s recognition and adaptation to various ligands and for a better understanding of the resistance of PR2 to most PR2 inhibitors, a major antiretroviral class. The PR recognizes various non-homologous substrates (Gag and Pol polyproteins) at several cleavage sites and PIs9 All these ligands are often asymmetric, and their binding is associated with large conformational changes resulting in a transition from a semi-open www.nature.com/scientificreports/. We compared the location of asymmetric positions with the ligand-binding pocket of PR2 to highlight structural asymmetry potentially induced by ligand binding This asymmetry is important for PR2’s adaptation to the ligand and for ligand recognition. Our results should improve the understanding of structural changes of PR2 and its adjustments to recognize and bind various inhibitors and the understanding of PR2 determinants to explain its resistance against some FDA-approved drugs
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