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| | <StructureSection load='7d0m' size='340' side='right'caption='[[7d0m]], [[Resolution|resolution]] 1.95Å' scene=''> | | <StructureSection load='7d0m' size='340' side='right'caption='[[7d0m]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7d0m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Lk3_transgenic_mice Lk3 transgenic mice]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D0M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D0M FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7d0m]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Mus_musculus Mus musculus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7D0M OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7D0M FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.95Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Cry1 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=10090 LK3 transgenic mice])</td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=PEG:DI(HYDROXYETHYL)ETHER'>PEG</scene>, <scene name='pdbligand=PG4:TETRAETHYLENE+GLYCOL'>PG4</scene></td></tr> |
| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d0m OCA], [https://pdbe.org/7d0m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d0m RCSB], [https://www.ebi.ac.uk/pdbsum/7d0m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d0m ProSAT]</span></td></tr> | | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=7d0m FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7d0m OCA], [https://pdbe.org/7d0m PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7d0m RCSB], [https://www.ebi.ac.uk/pdbsum/7d0m PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7d0m ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CRY1_MOUSE CRY1_MOUSE]] Blue light-dependent regulator of the circadian feedback loop. Inhibits CLOCK|NPAS2-ARNTL E box-mediated transcription. Acts, in conjunction with CRY2, in maintaining period length and circadian rhythmicity. Has no photolyase activity. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. May inhibit CLOCK|NPAS2-ARNTL transcriptional activity through stabilizing the unphosphorylated form of ARNTL.<ref>PMID:10428031</ref> <ref>PMID:16628007</ref> <ref>PMID:16478995</ref>
| + | [https://www.uniprot.org/uniprot/CRY1_MOUSE CRY1_MOUSE] Blue light-dependent regulator of the circadian feedback loop. Inhibits CLOCK|NPAS2-ARNTL E box-mediated transcription. Acts, in conjunction with CRY2, in maintaining period length and circadian rhythmicity. Has no photolyase activity. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. May inhibit CLOCK|NPAS2-ARNTL transcriptional activity through stabilizing the unphosphorylated form of ARNTL.<ref>PMID:10428031</ref> <ref>PMID:16628007</ref> <ref>PMID:16478995</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | </div> | | </div> |
| | <div class="pdbe-citations 7d0m" style="background-color:#fffaf0;"></div> | | <div class="pdbe-citations 7d0m" style="background-color:#fffaf0;"></div> |
| | + | |
| | + | ==See Also== |
| | + | *[[Cryptochrome 3D structures|Cryptochrome 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
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| | </StructureSection> | | </StructureSection> |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Lk3 transgenic mice]] | + | [[Category: Mus musculus]] |
| - | [[Category: Aikawa, Y]] | + | [[Category: Aikawa Y]] |
| - | [[Category: Hirota, T]] | + | [[Category: Hirota T]] |
| - | [[Category: Miller, S A]] | + | [[Category: Miller SA]] |
| - | [[Category: Circadian clock protein]]
| + | |
| - | [[Category: Cry]]
| + | |
| - | [[Category: Cry1]]
| + | |
| - | [[Category: Cryptochrome]]
| + | |
| - | [[Category: Phr]]
| + | |
| Structural highlights
Function
CRY1_MOUSE Blue light-dependent regulator of the circadian feedback loop. Inhibits CLOCK|NPAS2-ARNTL E box-mediated transcription. Acts, in conjunction with CRY2, in maintaining period length and circadian rhythmicity. Has no photolyase activity. Capable of translocating circadian clock core proteins such as PER proteins to the nucleus. May inhibit CLOCK|NPAS2-ARNTL transcriptional activity through stabilizing the unphosphorylated form of ARNTL.[1] [2] [3]
Publication Abstract from PubMed
The circadian clock is a biological timekeeper that operates through transcription-translation feedback loops in mammals. Cryptochrome 1 (CRY1) and Cryptochrome 2 (CRY2) are highly conserved core clock components having redundant and distinct functions. We recently identified the CRY1- and CRY2-selective compounds KL101 and TH301, respectively, which provide useful tools for the exploration of isoform-selective CRY regulation. However, intrinsic differences in the compound-binding FAD (flavin adenine dinucleotide) pockets between CRY1 and CRY2 are not well understood, partly because of nonoptimal properties of previously reported apo form structures in this particular region constituted by almost identical sequences. Here, we show unliganded CRY1 and CRY2 crystal structures with well-defined electron densities that are largely free of crystal contacts at the FAD pocket and nearby lid loop. We revealed conformational isomerism in key residues. In particular, CRY1 W399 and corresponding CRY2 W417 in the FAD pocket had distinct conformations ("out" for CRY1 and "in" for CRY2) by interacting with the lid loop residues CRY1 Q407 and CRY2 F424, respectively, resulting in different overall lid loop structures. Molecular dynamics simulations supported that these conformations were energetically favorable to each isoform. Isoform-selective compounds KL101 and TH301 preferred intrinsic "out" and "in" conformations of the tryptophan residue in CRY1 and CRY2, respectively, while the nonselective compound KL001 fit to both conformations. Mutations of lid loop residues designed to perturb their isoform-specific interaction with the tryptophan resulted in reversed responses of CRY1 and CRY2 to KL101 and TH301. We propose that these intrinsic structural differences of CRY1 and CRY2 can be targeted for isoform-selective regulation.
Structural differences in the FAD-binding pockets and lid loops of mammalian CRY1 and CRY2 for isoform-selective regulation.,Miller S, Srivastava A, Nagai Y, Aikawa Y, Tama F, Hirota T Proc Natl Acad Sci U S A. 2021 Jun 29;118(26). pii: 2026191118. doi:, 10.1073/pnas.2026191118. PMID:34172584[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Kume K, Zylka MJ, Sriram S, Shearman LP, Weaver DR, Jin X, Maywood ES, Hastings MH, Reppert SM. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell. 1999 Jul 23;98(2):193-205. PMID:10428031
- ↑ Kondratov RV, Kondratova AA, Lee C, Gorbacheva VY, Chernov MV, Antoch MP. Post-translational regulation of circadian transcriptional CLOCK(NPAS2)/BMAL1 complex by CRYPTOCHROMES. Cell Cycle. 2006 Apr;5(8):890-5. Epub 2006 Apr 17. PMID:16628007
- ↑ Chaves I, Yagita K, Barnhoorn S, Okamura H, van der Horst GT, Tamanini F. Functional evolution of the photolyase/cryptochrome protein family: importance of the C terminus of mammalian CRY1 for circadian core oscillator performance. Mol Cell Biol. 2006 Mar;26(5):1743-53. PMID:16478995 doi:10.1128/MCB.26.5.1743-1753.2006
- ↑ Miller S, Srivastava A, Nagai Y, Aikawa Y, Tama F, Hirota T. Structural differences in the FAD-binding pockets and lid loops of mammalian CRY1 and CRY2 for isoform-selective regulation. Proc Natl Acad Sci U S A. 2021 Jun 29;118(26). pii: 2026191118. doi:, 10.1073/pnas.2026191118. PMID:34172584 doi:http://dx.doi.org/10.1073/pnas.2026191118
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