Title

Probing Structural Changes among Analogous Inhibitor-Bound Forms of HIV-1 Protease and a Drug-Resistant Mutant in Solution by Nuclear Magnetic Resonance

UMMS Affiliation

Department of Biochemistry and Molecular Pharmacology; Schiffer Lab

Publication Date

2018-03-13

Document Type

Article

Disciplines

Amino Acids, Peptides, and Proteins | Biochemistry | Chemistry | Medicinal Chemistry and Pharmaceutics | Medicinal-Pharmaceutical Chemistry | Molecular Biology | Structural Biology

Abstract

In the era of state-of-the-art inhibitor design and high-resolution structural studies, detection of significant but small protein structural differences in the inhibitor-bound forms is critical to further developing the inhibitor. Here, we probed differences in HIV-1 protease (PR) conformation among darunavir and four analogous inhibitor-bound forms and compared them with a drug-resistant mutant using nuclear magnetic resonance chemical shifts. Changes in amide chemical shifts of wild-type (WT) PR among these inhibitor-bound forms, DeltaCSP, were subtle but detectable and extended > 10 A from the inhibitor-binding site, asymmetrically between the two subunits of PR. Molecular dynamics simulations revealed differential local hydrogen bonding as the molecular basis of this remote asymmetric change. Inhibitor-bound forms of the drug-resistant mutant also showed a similar long-range DeltaCSP pattern. Differences in DeltaCSP values of the WT and the mutant (DeltaDeltaCSPs) were observed at the inhibitor-binding site and in the surrounding region. Comparing chemical shift changes among highly analogous inhibitors and DeltaDeltaCSPs effectively eliminated local environmental effects stemming from different chemical groups and enabled exploitation of these sensitive parameters to detect subtle protein conformational changes and to elucidate asymmetric and remote conformational effects upon inhibitor interaction.

DOI of Published Version

10.1021/acs.biochem.7b01238

Source

Biochemistry. 2018 Mar 13;57(10):1652-1662. doi: 10.1021/acs.biochem.7b01238. Epub 2018 Feb 19. Link to article on publisher's site

Journal/Book/Conference Title

Biochemistry

Related Resources

Link to Article in PubMed

PubMed ID

29457713

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