Severity: Warning
Message: file_get_contents(https://...@gmail.com&api_key=61f08fa0b96a73de8c900d749fcb997acc09&a=1): Failed to open stream: HTTP request failed! HTTP/1.1 429 Too Many Requests
Filename: helpers/my_audit_helper.php
Line Number: 176
Backtrace:
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 176
Function: file_get_contents
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 250
Function: simplexml_load_file_from_url
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 1034
Function: getPubMedXML
File: /var/www/html/application/helpers/my_audit_helper.php
Line: 3152
Function: GetPubMedArticleOutput_2016
File: /var/www/html/application/controllers/Detail.php
Line: 575
Function: pubMedSearch_Global
File: /var/www/html/application/controllers/Detail.php
Line: 489
Function: pubMedGetRelatedKeyword
File: /var/www/html/index.php
Line: 316
Function: require_once
In patients with von-Hippel Lindau (VHL) disease, hypoxia-independent accumulation of HIF-2α leads to increased transcriptional activity of HIF-2α:ARNT that drives cancers such as renal cell carcinoma. Belzutifan, a recently FDA-approved drug, is designed to prevent the transcriptional activity of HIF-2α:ARNT, thereby overcoming the consequences of its unnatural accumulation in VHL-dependent cancers. Emerging evidence suggests that the naturally occurring variant G323E located in the HIF-2α drug binding pocket prevents inhibitory activity of belzutifan analogs, though the mechanism of inhibition remains unclear. Interestingly, proximal phosphorylation at neighboring T324, previously shown to regulate HIF-2 protein interactions, has also been proposed to affect HIF-2 drug binding. Here, we used molecular dynamics (MD) simulations to understand and compare the molecular-level effects of G323E and phospho-T324 (pT324) on the belzutifan bound-HIF-2α:ARNT complex. We find that both G323E and pT324 increase structural flexibility within the drug binding site and reduce the apparent binding affinity for belzutifan. Whereas the effects of G323E are concentrated in the binding pocket Fα helix within the HIF-2α PAS-B domain, pT324 decreased the belzutifan binding affinity and stabilized the HIF-2 heterodimer through an alternate mechanism involving polar interactions between the HIF-2α PAS-B and PAS-A domains. Further analysis via ensemble machine learning uncovered important and distinct interchain residue interactions modified by G323E and pT324. These findings reveal a molecular mechanism of G323E-induced drug resistance and suggest that pT324 may also affect the efficacy of HIF-2 drug binding interactions via allosteric effects.
Download full-text PDF |
Source |
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11391435 | PMC |
http://dx.doi.org/10.1021/acsomega.4c03777 | DOI Listing |
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