Unveiling a Hidden Pocket in HIV-1 Protease: New Insights Into Retroviral Protease Cantilever-Tip Region Characteristics.

HIV protease binding site cryptic cantilever pocket fragment‐based screening molecular dynamics simulations retroviruses

Journal

Proteins

ISSN: 1097-0134

Titre abrégé: Proteins

Pays: United States

ID NLM: 8700181

Informations de publication

Date de publication:
07 Aug 2024

Historique:

revised: 11 07 2024

received: 04 04 2024

accepted: 15 07 2024

medline: 7 8 2024

pubmed: 7 8 2024

entrez: 7 8 2024

Statut: aheadofprint

Résumé

The HIV-1 protease is critical for the process of viral maturation and as such, it is one of the most well characterized proteins in the Protein Data Bank. There is some evidence to suggest that the HIV-1 protease is capable of accommodating small molecule fragments at several locations on its surface outside of the active site. However, some pockets on the surface of proteins remain unformed in the apo structure and are termed "cryptic sites." To date, no cryptic sites have been identified in the structure of HIV-1 protease. Here, we characterize a novel cryptic cantilever pocket on the surface of the HIV-1 protease through mixed-solvent molecular dynamics simulations using several probes. Interestingly, we noted that several homologous retroviral proteases exhibit evolutionarily conserved dynamics in the cantilever region and possess a conserved pocket in the cantilever region. Immobilization of the cantilever region of the HIV-1 protease via disulfide cross-linking resulted in curling-in of the flap tips and the propensity for the protease to adopt a semi-open flap conformation. Structure-based analysis and fragment-based screening of the cryptic cantilever pocket suggested that the pocket may be capable of accommodating ligand structures. Furthermore, molecular dynamics simulations of a top scoring fragment bound to the cryptic pocket illustrated altered flap dynamics of the fragment-bound enzyme. Together, these results suggest that the mobility of the cantilever region plays a key role in the global dynamics of retroviral proteases. Therefore, the cryptic cantilever pocket of the HIV-1 protease may represent an interesting target for future in vitro studies.

Identifiants

DOI: 10.1002/prot.26735 PMID: 39109919

pubmed: 39109919

doi: 10.1002/prot.26735

doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Subventions

Organisme : South African Medical Research Council

Organisme : South African National Research Foundation (NRF)

ID : CPRR210118582137

Informations de copyright

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