6pw3: Difference between revisions

Latest revision as of 07:36, 11 October 2023

LARP1 DM15 FYRE (F844Y, R847E) mutant bound to m7GpppG dinucleotide (capG)

Structural highlights

6pw3 is a 4 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 2.34Å
Ligands:	GTG, MG
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LARP1_HUMAN RNA-binding protein that promotes translation of specific classes of mRNAs downstream of the mTORC1 complex. Associates with the mRNA 5'cap in an MTOR-dependent manner and associates with mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding for ribosomal proteins and several components of the translation machinery. Associates with actively translating ribosomes via interaction with PABPC1/PABP and stimulates translation of mRNAs containing a 5'TOP, thereby regulating cell growth and proliferation.^[1] ^[2] ^[3]

Publication Abstract from PubMed

The RNA-binding protein La-related protein 1 (LARP1) plays a central role in ribosome biosynthesis. Its C-terminal DM15 region binds the 7-methylguanosine (m(7)G) cap and 5' terminal oligopyrimidine (TOP) motif characteristic of transcripts encoding ribosomal proteins and translation factors. Under the control of mammalian target of rapamycin complex 1 (mTORC1), LARP1 regulates translation of these transcripts. Characterizing the dynamics of DM15-TOP recognition is essential to understanding this fundamental biological process. We use molecular dynamics simulations, biophysical assays, and X-ray crystallography to reveal the mechanism of DM15 binding to TOP transcripts. Residues C-terminal to the m(7)G-binding site play important roles in cap recognition. Furthermore, we show that the unusually static pocket that recognizes the +1 cytosine characteristic of TOP transcripts drives binding specificity. Finally, we demonstrate that the DM15 pockets involved in TOP-specific m(7)GpppC-motif recognition are likely druggable. Collectively, these studies suggest unique opportunities for further pharmacological development.

Capturing the Mechanism Underlying TOP mRNA Binding to LARP1.,Cassidy KC, Lahr RM, Kaminsky JC, Mack S, Fonseca BD, Das SR, Berman AJ, Durrant JD Structure. 2019 Oct 29. pii: S0969-2126(19)30347-8. doi:, 10.1016/j.str.2019.10.006. PMID:31676287^[4]

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

References

↑ Burrows C, Abd Latip N, Lam SJ, Carpenter L, Sawicka K, Tzolovsky G, Gabra H, Bushell M, Glover DM, Willis AE, Blagden SP. The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration. Nucleic Acids Res. 2010 Sep;38(16):5542-53. doi: 10.1093/nar/gkq294. Epub 2010, Apr 29. PMID:20430826 doi:https://dx.doi.org/10.1093/nar/gkq294
↑ Aoki K, Adachi S, Homoto M, Kusano H, Koike K, Natsume T. LARP1 specifically recognizes the 3' terminus of poly(A) mRNA. FEBS Lett. 2013 Jul 11;587(14):2173-8. doi: 10.1016/j.febslet.2013.05.035. Epub, 2013 May 24. PMID:23711370 doi:https://dx.doi.org/10.1016/j.febslet.2013.05.035
↑ Tcherkezian J, Cargnello M, Romeo Y, Huttlin EL, Lavoie G, Gygi SP, Roux PP. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation. Genes Dev. 2014 Feb 15;28(4):357-71. doi: 10.1101/gad.231407.113. PMID:24532714 doi:https://dx.doi.org/10.1101/gad.231407.113
↑ Cassidy KC, Lahr RM, Kaminsky JC, Mack S, Fonseca BD, Das SR, Berman AJ, Durrant JD. Capturing the Mechanism Underlying TOP mRNA Binding to LARP1. Structure. 2019 Oct 29. pii: S0969-2126(19)30347-8. doi:, 10.1016/j.str.2019.10.006. PMID:31676287 doi:https://dx.doi.org/10.1016/j.str.2019.10.006

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OCA

[1] Burrows C, Abd Latip N, Lam SJ, Carpenter L, Sawicka K, Tzolovsky G, Gabra H, Bushell M, Glover DM, Willis AE, Blagden SP. The RNA binding protein Larp1 regulates cell division, apoptosis and cell migration. Nucleic Acids Res. 2010 Sep;38(16):5542-53. doi: 10.1093/nar/gkq294. Epub 2010, Apr 29. PMID:20430826 doi:https://dx.doi.org/10.1093/nar/gkq294

[2] Aoki K, Adachi S, Homoto M, Kusano H, Koike K, Natsume T. LARP1 specifically recognizes the 3' terminus of poly(A) mRNA. FEBS Lett. 2013 Jul 11;587(14):2173-8. doi: 10.1016/j.febslet.2013.05.035. Epub, 2013 May 24. PMID:23711370 doi:https://dx.doi.org/10.1016/j.febslet.2013.05.035

[3] Tcherkezian J, Cargnello M, Romeo Y, Huttlin EL, Lavoie G, Gygi SP, Roux PP. Proteomic analysis of cap-dependent translation identifies LARP1 as a key regulator of 5'TOP mRNA translation. Genes Dev. 2014 Feb 15;28(4):357-71. doi: 10.1101/gad.231407.113. PMID:24532714 doi:https://dx.doi.org/10.1101/gad.231407.113

[4] Cassidy KC, Lahr RM, Kaminsky JC, Mack S, Fonseca BD, Das SR, Berman AJ, Durrant JD. Capturing the Mechanism Underlying TOP mRNA Binding to LARP1. Structure. 2019 Oct 29. pii: S0969-2126(19)30347-8. doi:, 10.1016/j.str.2019.10.006. PMID:31676287 doi:https://dx.doi.org/10.1016/j.str.2019.10.006

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[2]

[3]

[4]

@@ Line 3: / Line 3: @@
 <StructureSection load='6pw3' size='340' side='right'caption='[[6pw3]], [[Resolution|resolution]] 2.34&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6pw3]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PW3 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6PW3 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6pw3]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6PW3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6PW3 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GTG:7-METHYL-GUANOSINE-5-TRIPHOSPHATE-5-GUANOSINE'>GTG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</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]] 2.34&#8491;</td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LARP1, KIAA0731, LARP ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GTG:7-METHYL-GUANOSINE-5-TRIPHOSPHATE-5-GUANOSINE'>GTG</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6pw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pw3 OCA], [http://pdbe.org/6pw3 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6pw3 RCSB], [http://www.ebi.ac.uk/pdbsum/6pw3 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6pw3 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=6pw3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6pw3 OCA], [https://pdbe.org/6pw3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6pw3 RCSB], [https://www.ebi.ac.uk/pdbsum/6pw3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6pw3 ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/LARP1_HUMAN LARP1_HUMAN]] RNA-binding protein that promotes translation of specific classes of mRNAs downstream of the mTORC1 complex. Associates with the mRNA 5'cap in an MTOR-dependent manner and associates with mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding for ribosomal proteins and several components of the translation machinery. Associates with actively translating ribosomes via interaction with PABPC1/PABP and stimulates translation of mRNAs containing a 5'TOP, thereby regulating cell growth and proliferation.<ref>PMID:20430826</ref> <ref>PMID:23711370</ref> <ref>PMID:24532714</ref>
+[https://www.uniprot.org/uniprot/LARP1_HUMAN LARP1_HUMAN] RNA-binding protein that promotes translation of specific classes of mRNAs downstream of the mTORC1 complex. Associates with the mRNA 5'cap in an MTOR-dependent manner and associates with mRNAs containing a 5' terminal oligopyrimidine (5'TOP) motif, which is present in mRNAs encoding for ribosomal proteins and several components of the translation machinery. Associates with actively translating ribosomes via interaction with PABPC1/PABP and stimulates translation of mRNAs containing a 5'TOP, thereby regulating cell growth and proliferation.<ref>PMID:20430826</ref> <ref>PMID:23711370</ref> <ref>PMID:24532714</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 23: / Line 23: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Berman, A J]]
+[[Category: Berman AJ]]
-[[Category: Lahr, R M]]
+[[Category: Lahr RM]]
-[[Category: Cap-binding]]
-[[Category: Heat-like]]
-[[Category: Rna binding protein]]
-[[Category: Top mrna]]
-[[Category: Translation regulation]]

6pw3: Difference between revisions

Latest revision as of 07:36, 11 October 2023

LARP1 DM15 FYRE (F844Y, R847E) mutant bound to m7GpppG dinucleotide (capG)

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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