6i2p
From Proteopedia
(Difference between revisions)
| Line 1: | Line 1: | ||
| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of the Mycobacterium tuberculosis PknB kinase domain (L33E mutant) in complex with its substrate GarA== | |
| + | <StructureSection load='6i2p' size='340' side='right'caption='[[6i2p]], [[Resolution|resolution]] 2.37Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6i2p]] is a 5 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6I2P OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6I2P FirstGlance]. <br> | ||
| + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACP:PHOSPHOMETHYLPHOSPHONIC+ACID+ADENYLATE+ESTER'>ACP</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr> | ||
| + | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=TPO:PHOSPHOTHREONINE'>TPO</scene>, <scene name='pdbligand=UNK:UNKNOWN'>UNK</scene></td></tr> | ||
| + | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></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=6i2p FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6i2p OCA], [http://pdbe.org/6i2p PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6i2p RCSB], [http://www.ebi.ac.uk/pdbsum/6i2p PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6i2p ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [[http://www.uniprot.org/uniprot/PKNB_MYCTU PKNB_MYCTU]] Key component of a signal transduction pathway that regulates cell growth and cell division via phosphorylation of target proteins such as GarA, GlmU, PapA5, PbpA, FhaB (Rv0019c), FhaA (Rv0020c), MviN, PstP, EmbR, Rv1422, Rv1747 and RseA. Shows a strong preference for Thr versus Ser as the phosphoacceptor.<ref>PMID:15985609</ref> <ref>PMID:15978616</ref> <ref>PMID:15987910</ref> <ref>PMID:16817899</ref> <ref>PMID:16980473</ref> <ref>PMID:16436437</ref> <ref>PMID:19826007</ref> <ref>PMID:19121323</ref> <ref>PMID:20025669</ref> <ref>PMID:21423706</ref> <ref>PMID:22275220</ref> [[http://www.uniprot.org/uniprot/GARA_MYCTU GARA_MYCTU]] Involved in regulation of glutamate metabolism. Acts as a phosphorylation-dependent molecular switch that modulates the activities of Kgd, Gdh and GltB.<ref>PMID:19019160</ref> <ref>PMID:19114043</ref> <ref>PMID:19318624</ref> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Forkhead-associated (FHA) domains are modules that bind to phosphothreonine (pThr) residues in signaling cascades. The FHA-containing mycobacterial protein GarA is a central element of a phosphorylation-dependent signaling pathway that redirects metabolic flux in response to amino acid starvation or cell growth requirements. GarA acts as a phosphorylation-dependent ON/OFF molecular switch. In its nonphosphorylated ON state, the GarA FHA domain engages in phosphorylation-independent interactions with various metabolic enzymes that orchestrate nitrogen flow, such as 2-oxoglutarate decarboxylase (KGD). However, phosphorylation at the GarA N-terminal region by the protein kinase PknB or PknG triggers autoinhibition through the intramolecular association of the N-terminal domain with the FHA domain, thus blocking all downstream interactions. To investigate these different FHA binding modes, we solved the crystal structures of the mycobacterial upstream (phosphorylation-dependent) complex PknB-GarA and the downstream (phosphorylation-independent) complex GarA-KGD. Our results show that the phosphorylated activation loop of PknB serves as a docking site to recruit GarA through canonical FHA-pThr interactions. However, the same GarA FHA-binding pocket targets an allosteric site on nonphosphorylated KGD, where a key element of recognition is a phosphomimetic aspartate. Further enzymatic and mutagenesis studies revealed that GarA acted as a dynamic allosteric inhibitor of KGD by preventing crucial motions in KGD that are necessary for catalysis. Our results provide evidence for physiological phosphomimetics, supporting numerous mutagenesis studies using such approaches, and illustrate how evolution can shape a single FHA-binding pocket to specifically interact with multiple phosphorylated and nonphosphorylated protein partners. | ||
| - | + | Structural insights into the functional versatility of an FHA domain protein in mycobacterial signaling.,Wagner T, Andre-Leroux G, Hindie V, Barilone N, Lisa MN, Hoos S, Raynal B, Vulliez-Le Normand B, O'Hare HM, Bellinzoni M, Alzari PM Sci Signal. 2019 May 7;12(580). pii: 12/580/eaav9504. doi:, 10.1126/scisignal.aav9504. PMID:31064884<ref>PMID:31064884</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: | + | <div class="pdbe-citations 6i2p" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Non-specific serine/threonine protein kinase]] | ||
| + | [[Category: Alzari, P M]] | ||
[[Category: Andre-Leroux, G]] | [[Category: Andre-Leroux, G]] | ||
[[Category: Barilone, N]] | [[Category: Barilone, N]] | ||
| + | [[Category: Bellinzoni, M]] | ||
[[Category: Hindie, V]] | [[Category: Hindie, V]] | ||
| + | [[Category: Fha-domain protein]] | ||
| + | [[Category: Kinase]] | ||
| + | [[Category: Signaling protein]] | ||
Revision as of 06:48, 23 May 2019
Crystal structure of the Mycobacterium tuberculosis PknB kinase domain (L33E mutant) in complex with its substrate GarA
| |||||||||||
