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Related Concept Videos

Cooperative Allosteric Transitions01:58

Cooperative Allosteric Transitions

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Cooperative allosteric transitions can occur in multimeric proteins, where each subunit of the protein has its own ligand-binding site. When a ligand binds to any of these subunits, it triggers a conformational change that affects the binding sites in the other subunits; this can change the affinity of the other sites for their respective ligands. The ability of the protein to change the shape of its binding site is attributed to the presence of a mix of flexible and stable segments in the...
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Allosteric Regulation01:08

Allosteric Regulation

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Allosteric regulation of enzymes occurs when the binding of an effector molecule to a site that is different from the active site causes a change in the enzymatic activity. This alternate site is called an allosteric site, and an enzyme can contain more than one of these sites. Allosteric regulation can either be positive or negative, resulting in an increase or decrease in enzyme activity. Most enzymes that display allosteric regulation are metabolic enzymes involved in the degradation or...
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Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

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Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl...
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General Transcription Factors01:30

General Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Master Transcription Regulators02:23

Master Transcription Regulators

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Master transcription regulators are regulatory proteins that are predominantly responsible for regulating the expression of multiple genes. Often these genes work in concert to drive a  complex process. Activation of a master transcription regulator can lead to a cascade of transcriptional activation necessary for that outcome. These regulators can directly bind to the regulatory sequences of the various genes involved, or they can indirectly regulate transcription by binding to regulatory...
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Transcription Factors02:16

Transcription Factors

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Tissue-specific transcription factors contribute to diverse cellular functions in mammals. For example, the gene for beta globin, a major component of hemoglobin, is present in all cells of the body. However, it is only expressed in red blood cells because the transcription factors that can bind to the promoter sequences of the beta globin gene are only expressed in these cells. Tissue-specific transcription factors also ensure that mutations in these factors may impair only the function of...
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Updated: Jul 11, 2025

Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions
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Co-immunoprecipitation Assay Using Endogenous Nuclear Proteins from Cells Cultured Under Hypoxic Conditions

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Decoding Allosteric Control in Hypoxia-Inducible Factors.

Jingjing Zhuang1, Qinghong Shang2, Fraydoon Rastinejad3

  • 1Marine College, Shandong University, Weihai 264209, China; Helmholtz International Lab, State Key Laboratory of Microbial Technology, Shandong University, Qingdao 266237, China.

Journal of Molecular Biology
|November 7, 2023
PubMed
Summary
This summary is machine-generated.

Basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) proteins regulate cellular responses. Understanding their structure and allosteric mechanisms, particularly in hypoxia-inducible factors (HIFs), promises new therapeutic drug discovery.

Keywords:
PAS domainallosteric effectbHLH-PAS transcription factorshypoxia-inducible factorsligand-binding pocket

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Area of Science:

  • Molecular biology
  • Structural biology
  • Biochemistry

Background:

  • Mammalian bHLH-PAS transcription factors sense environmental and physiological signals.
  • These proteins form dimers via bHLH domains for DNA binding.
  • The bHLH-PAS family is implicated in major human diseases, presenting therapeutic targets.

Purpose of the Study:

  • To review the structural and allosteric mechanisms of the HIF subfamily of bHLH-PAS proteins.
  • To highlight the potential for targeted small molecule drug development.

Main Methods:

  • Analysis of crystal structures of HIF-α proteins and their interaction with ARNT.
  • Review of recent findings on allosteric modulation by small molecules.

Main Results:

  • The crystal structures of HIF-α proteins reveal their interaction with ARNT.
  • Small molecules binding to PAS-B domains allosterically modulate HIF-α transcriptional activity.
  • Approved drugs like Belzutifan and Tapinarof target bHLH-PAS proteins.

Conclusions:

  • Understanding bHLH-PAS protein architecture and allostery is key to drug discovery.
  • Targeting ligand-binding cavities in PAS domains enables the development of novel therapeutics.
  • Advances in this field offer promising avenues for treating diseases linked to bHLH-PAS dysfunction.