7td7: Difference between revisions
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==Crystal structure of an E. coli thiM riboswitch bound to thiamine, manganese ions== | ==Crystal structure of an E. coli thiM riboswitch bound to thiamine, manganese ions== | ||
<StructureSection load='7td7' size='340' side='right'caption='[[7td7]]' scene=''> | <StructureSection load='7td7' size='340' side='right'caption='[[7td7]], [[Resolution|resolution]] 2.95Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TD7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7td7]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7TD7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7TD7 FirstGlance]. <br> | ||
</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=7td7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7td7 OCA], [https://pdbe.org/7td7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7td7 RCSB], [https://www.ebi.ac.uk/pdbsum/7td7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7td7 ProSAT]</span></td></tr> | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=MN:MANGANESE+(II)+ION'>MN</scene>, <scene name='pdbligand=VIB:3-(4-AMINO-2-METHYL-PYRIMIDIN-5-YLMETHYL)-5-(2-HYDROXY-ETHYL)-4-METHYL-THIAZOL-3-IUM'>VIB</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=7td7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7td7 OCA], [https://pdbe.org/7td7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7td7 RCSB], [https://www.ebi.ac.uk/pdbsum/7td7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7td7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
RNA molecules can show high levels of cooperativity in their global folding and interactions with divalent ions. However, cooperativity at individual ligand-RNA interaction sites remains poorly understood. Here, we investigated the binding of thiamine and methylene diphosphonic acid (MDP, a soluble structural analogue of pyrophosphate) to the thiamine pyrophosphate riboswitch. These ligands each bind weakly at proximal subsites, with 10 muM and 1 mM affinities, respectively. The affinity of MDP moderately improves when thiamine or thiamine-like fragments are pre-bound to the RNA. Covalent linking of thiamine and MDP substantially increases riboswitch binding to a notable high affinity of 20 nM. Crystal structures and single-molecule correlated chemical probing revealed favorable induced fit effects upon binding of individual ligands and, unexpectedly, a substantial thermodynamically unfavorable RNA structural rearrangement upon binding of the linked thiamine-MDP ligand. Thus, linking of two ligands of modest affinity, accompanied by an unfavorable structural rearrangement, still yields a potent linked RNA-binding compound. Since complex ligands often bind riboswitches and other RNAs at proximal subsites, principles derived from this work inform and support fragment-linking strategies for identifying small molecules that interact with RNA specifically and with high affinity. | |||
Subsite Ligand Recognition and Cooperativity in the TPP Riboswitch: Implications for Fragment-Linking in RNA Ligand Discovery.,Zeller MJ, Nuthanakanti A, Li K, Aube J, Serganov A, Weeks KM ACS Chem Biol. 2022 Jan 21. doi: 10.1021/acschembio.1c00880. PMID:35060698<ref>PMID:35060698</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7td7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Nuthanakanti A]] | [[Category: Nuthanakanti, A]] | ||
[[Category: Serganov A]] | [[Category: Serganov, A]] | ||
[[Category: Rna]] | |||
Revision as of 10:32, 2 March 2022
Crystal structure of an E. coli thiM riboswitch bound to thiamine, manganese ionsCrystal structure of an E. coli thiM riboswitch bound to thiamine, manganese ions
Structural highlights
Publication Abstract from PubMedRNA molecules can show high levels of cooperativity in their global folding and interactions with divalent ions. However, cooperativity at individual ligand-RNA interaction sites remains poorly understood. Here, we investigated the binding of thiamine and methylene diphosphonic acid (MDP, a soluble structural analogue of pyrophosphate) to the thiamine pyrophosphate riboswitch. These ligands each bind weakly at proximal subsites, with 10 muM and 1 mM affinities, respectively. The affinity of MDP moderately improves when thiamine or thiamine-like fragments are pre-bound to the RNA. Covalent linking of thiamine and MDP substantially increases riboswitch binding to a notable high affinity of 20 nM. Crystal structures and single-molecule correlated chemical probing revealed favorable induced fit effects upon binding of individual ligands and, unexpectedly, a substantial thermodynamically unfavorable RNA structural rearrangement upon binding of the linked thiamine-MDP ligand. Thus, linking of two ligands of modest affinity, accompanied by an unfavorable structural rearrangement, still yields a potent linked RNA-binding compound. Since complex ligands often bind riboswitches and other RNAs at proximal subsites, principles derived from this work inform and support fragment-linking strategies for identifying small molecules that interact with RNA specifically and with high affinity. Subsite Ligand Recognition and Cooperativity in the TPP Riboswitch: Implications for Fragment-Linking in RNA Ligand Discovery.,Zeller MJ, Nuthanakanti A, Li K, Aube J, Serganov A, Weeks KM ACS Chem Biol. 2022 Jan 21. doi: 10.1021/acschembio.1c00880. PMID:35060698[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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