6kx6: Difference between revisions

Latest revision as of 10:45, 22 November 2023

Crystal structure of mouse Cryptochrome 1 in complex with KL101 compound

Structural highlights

6kx6 is a 2 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2Å
Ligands:	DYU
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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

CRY1 and CRY2 are essential components of the circadian clock controlling daily physiological rhythms. Accumulating evidences indicate distinct roles of these highly homologous proteins, in addition to redundant functions. Therefore, the development of isoform-selective compounds represents an effective approach towards understanding the similarities and differences of CRY1 and CRY2 by controlling each isoform individually. We conducted phenotypic screenings of circadian clock modulators, and identified KL101 and TH301 that selectively stabilize CRY1 and CRY2, respectively. Crystal structures of CRY-compound complexes revealed conservation of compound-binding sites between CRY1 and CRY2. We further discovered a unique mechanism underlying compound selectivity in which the disordered C-terminal region outside the pocket was required for the differential effects of KL101 and TH301 against CRY isoforms. By using these compounds, we found a new role of CRY1 and CRY2 as enhancers of brown adipocyte differentiation, providing the basis of CRY-mediated regulation of energy expenditure.

Isoform-selective regulation of mammalian cryptochromes.,Miller S, Son YL, Aikawa Y, Makino E, Nagai Y, Srivastava A, Oshima T, Sugiyama A, Hara A, Abe K, Hirata K, Oishi S, Hagihara S, Sato A, Tama F, Itami K, Kay SA, Hatori M, Hirota T Nat Chem Biol. 2020 Mar 30. pii: 10.1038/s41589-020-0505-1. doi:, 10.1038/s41589-020-0505-1. PMID:32231341^[4]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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, Son YL, Aikawa Y, Makino E, Nagai Y, Srivastava A, Oshima T, Sugiyama A, Hara A, Abe K, Hirata K, Oishi S, Hagihara S, Sato A, Tama F, Itami K, Kay SA, Hatori M, Hirota T. Isoform-selective regulation of mammalian cryptochromes. Nat Chem Biol. 2020 Mar 30. pii: 10.1038/s41589-020-0505-1. doi:, 10.1038/s41589-020-0505-1. PMID:32231341 doi:https://dx.doi.org/10.1038/s41589-020-0505-1

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] 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

[2] 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

[3] 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

[4] Miller S, Son YL, Aikawa Y, Makino E, Nagai Y, Srivastava A, Oshima T, Sugiyama A, Hara A, Abe K, Hirata K, Oishi S, Hagihara S, Sato A, Tama F, Itami K, Kay SA, Hatori M, Hirota T. Isoform-selective regulation of mammalian cryptochromes. Nat Chem Biol. 2020 Mar 30. pii: 10.1038/s41589-020-0505-1. doi:, 10.1038/s41589-020-0505-1. PMID:32231341 doi:https://dx.doi.org/10.1038/s41589-020-0505-1

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[2]

[3]

[4]

@@ Line 3: / Line 3: @@
 <StructureSection load='6kx6' size='340' side='right'caption='[[6kx6]], [[Resolution|resolution]] 2.00&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6kx6]] is a 2 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=6KX6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KX6 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6kx6]] is a 2 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=6KX6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6KX6 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DYU:~{N}-[2-(2,4-dimethylphenyl)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-3,4-dimethyl-benzamide'>DYU</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]] 2&#8491;</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=DYU:~{N}-[2-(2,4-dimethylphenyl)-4,6-dihydrothieno[3,4-c]pyrazol-3-yl]-3,4-dimethyl-benzamide'>DYU</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=6kx6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6kx6 OCA], [https://pdbe.org/6kx6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6kx6 RCSB], [https://www.ebi.ac.uk/pdbsum/6kx6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6kx6 ProSAT]</span></td></tr>
 </table>
 == 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;">
 == Publication Abstract from PubMed ==
@@ Line 27: / Line 27: @@
 </StructureSection>
 [[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]]

6kx6: Difference between revisions

Latest revision as of 10:45, 22 November 2023

Crystal structure of mouse Cryptochrome 1 in complex with KL101 compound

Structural highlights

Function

Publication Abstract from PubMed

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References

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