NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors
The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 mus...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2016-10-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/18790 |
| _version_ | 1811253319603060736 |
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| author | Dalei Wu Xiaoyu Su Nalini Potluri Youngchang Kim Fraydoon Rastinejad |
| author_facet | Dalei Wu Xiaoyu Su Nalini Potluri Youngchang Kim Fraydoon Rastinejad |
| author_sort | Dalei Wu |
| collection | DOAJ |
| description | The neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs. |
| first_indexed | 2024-04-12T16:49:03Z |
| format | Article |
| id | doaj.art-a01d3417dd4544bab75fc6286baaba62 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:49:03Z |
| publishDate | 2016-10-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-a01d3417dd4544bab75fc6286baaba622022-12-22T03:24:27ZengeLife Sciences Publications LtdeLife2050-084X2016-10-01510.7554/eLife.18790NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factorsDalei Wu0Xiaoyu Su1Nalini Potluri2Youngchang Kim3Fraydoon Rastinejad4https://orcid.org/0000-0002-0784-9352Integrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United StatesIntegrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United StatesIntegrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United StatesStructural Biology Center, Biosciences Division, Argonne National Laboratory, Argonne, United StatesIntegrative Metabolism Program, Sanford Burnham Prebys Medical Discovery Institute, Orlando, United StatesThe neuronal PAS domain proteins NPAS1 and NPAS3 are members of the basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family, and their genetic deficiencies are linked to a variety of human psychiatric disorders including schizophrenia, autism spectrum disorders and bipolar disease. NPAS1 and NPAS3 must each heterodimerize with the aryl hydrocarbon receptor nuclear translocator (ARNT), to form functional transcription complexes capable of DNA binding and gene regulation. Here we examined the crystal structures of multi-domain NPAS1-ARNT and NPAS3-ARNT-DNA complexes, discovering each to contain four putative ligand-binding pockets. Through expanded architectural comparisons between these complexes and HIF-1α-ARNT, HIF-2α-ARNT and CLOCK-BMAL1, we show the wider mammalian bHLH-PAS family is capable of multi-ligand-binding and presents as an ideal class of transcription factors for direct targeting by small-molecule drugs.https://elifesciences.org/articles/18790PAS domainsNeuronal PAS ProteinsbHLH-PAS proteinsligand binding pocketscrystal structurepsychiatric disorders |
| spellingShingle | Dalei Wu Xiaoyu Su Nalini Potluri Youngchang Kim Fraydoon Rastinejad NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors eLife PAS domains Neuronal PAS Proteins bHLH-PAS proteins ligand binding pockets crystal structure psychiatric disorders |
| title | NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors |
| title_full | NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors |
| title_fullStr | NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors |
| title_full_unstemmed | NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors |
| title_short | NPAS1-ARNT and NPAS3-ARNT crystal structures implicate the bHLH-PAS family as multi-ligand binding transcription factors |
| title_sort | npas1 arnt and npas3 arnt crystal structures implicate the bhlh pas family as multi ligand binding transcription factors |
| topic | PAS domains Neuronal PAS Proteins bHLH-PAS proteins ligand binding pockets crystal structure psychiatric disorders |
| url | https://elifesciences.org/articles/18790 |
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