Ligand-induced perturbation of the HIF-2α:ARNT dimer dynamics

PLoS Computational Biology
Stefano MottaAlessandro Pandini

Abstract

Hypoxia inducible factors (HIFs) are transcription factors belonging to the basic helix-loop-helix PER-ARNT-SIM (bHLH-PAS) protein family with a role in sensing oxygen levels in the cell. Under hypoxia, the HIF-α degradation pathway is blocked and dimerization with the aryl hydrocarbon receptor nuclear translocator (ARNT) makes HIF-α transcriptionally active. Due to the common hypoxic environment of tumors, inhibition of this mechanism by destabilization of HIF-α:ARNT dimerization has been proposed as a promising therapeutic strategy. Following the discovery of a druggable cavity within the PAS-B domain of HIF-2α, research efforts have been directed to identify artificial ligands that can impair heterodimerization. Although the crystallographic structures of the HIF-2α:ARNT complex have elucidated the dimer architecture and the 0X3-inhibitor placement within the HIF-2α PAS-B, unveiling the inhibition mechanism requires investigation of how ligand-induced perturbations could dynamically propagate through the structure and affect dimerization. To this end, we compared evolutionary features, intrinsic dynamics and energetic properties of the dimerization interfaces of HIF-2α:ARNT in both the apo and holo forms. Residue conservatio...Continue Reading

References

May 20, 1994·Journal of Molecular Biology·I K McDonald, J M Thornton
Sep 1, 1997·Nucleic Acids Research·S F AltschulD J Lipman
Jun 5, 1999·Microbiology and Molecular Biology Reviews : MMBR·B L Taylor, I B Zhulin
Oct 6, 1999·Current Opinion in Genetics & Development·S T Crews, C M Fan
Dec 11, 1999·Nucleic Acids Research·H M BermanP E Bourne
Oct 25, 2000·Protein Science : a Publication of the Protein Society·A FiserA Sali
Sep 13, 2003·Science·Shannon M HarperKevin H Gardner
Dec 4, 2003·The International Journal of Biochemistry & Cell Biology·Robyn J KewleyAnne Chapman-Smith
Dec 12, 2003·Proceedings of the National Academy of Sciences of the United States of America·Paul J A ErbelKevin H Gardner
Apr 30, 2004·Journal of Computational Chemistry·Junmei WangDavid A Case
Sep 1, 2005·The Journal of Biological Chemistry·Jinsong YangRichard K Bruick
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Aug 31, 2006·Bioinformatics·Barry J GrantLeo S D Caves
Jan 11, 2007·The Journal of Chemical Physics·Giovanni BussiMichele Parrinello
May 27, 2008·Nature Reviews. Cancer·Mark W DewhirstBenjamin Moeller
Oct 31, 2008·Nucleic Acids Research·Ofir GoldenbergNir Ben-Tal
Jan 9, 2009·Proceedings of the National Academy of Sciences of the United States of America·Thomas H ScheuermannKevin H Gardner
Feb 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·Matthew R EvansKevin H Gardner
Apr 9, 2009·Proceedings of the National Academy of Sciences of the United States of America·Anurag SethiZaida Luthey-Schulten
Oct 7, 2009·Proceedings of the National Academy of Sciences of the United States of America·KangAe LeeGregg L Semenza
Oct 20, 2009·Structure·Andreas MöglichKeith Moffat
Dec 3, 2009·Journal of the American Chemical Society·Jason KeyKevin H Gardner
Apr 1, 2010·Nature Methods·Ivan A AdzhubeiShamil R Sunyaev
Apr 17, 2010·Current Opinion in Chemical Biology·Angela N Koehler
May 17, 2011·BMC Bioinformatics·Domenico FraccalvieriLaura Bonati
Sep 13, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Michael S DenisonBin Zhao
Oct 13, 2011·Molecular Systems Biology·Fabian SieversDesmond G Higgins
Dec 16, 2011·Nature Reviews. Cancer·Brian KeithM Celeste Simon
Feb 1, 2013·Journal of Medicinal Chemistry·Jamie L RogersUttam K Tambar
Feb 26, 2013·Nature Chemical Biology·Thomas H ScheuermannRichard K Bruick
Apr 4, 2013·Current Topics in Medicinal Chemistry·Alessandro PandiniLaura Bonati
Apr 13, 2013·Journal of Computer-aided Molecular Design·G Madhavi SastryWoody Sherman
Nov 20, 2013·Journal of Chemical Theory and Computation·Arianna ForniliFranca Fraternali
Nov 23, 2013·Nature Reviews. Cancer·David C BerstenMurray L Whitelaw

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Citations

Jun 1, 2019·PLoS Computational Biology·Alessandro PandiniShahid Khan
Apr 8, 2020·International Journal of Molecular Sciences·Anatoly A SoshilovMichael S Denison
Jul 25, 2019·Scientific Reports·Sara Giani TagliabueLaura Bonati
Sep 7, 2020·Biophysical Journal·Paige WheatleyShahid Khan
Mar 30, 2021·Journal of Chemical Theory and Computation·Stefano MottaLaura Bonati
Jun 5, 2021·Journal of Chemical Theory and Computation·Lara CalleaStefano Motta
Dec 8, 2021·Development·Yida JiangGuo-Hua Fong

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Methods Mentioned

BETA
NMR
X-ray
co-immunoprecipitation
co-IP

Software Mentioned

GROMACS
Modeller
Bio3D package
PROPKA
SIFT
Clustal Omega
Rosetta
ConSurf
GBSA
MM

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