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==Crystal structure of human adenylate kinase 3, AK3, in complex with inhibitor Gp5A== | ==Crystal structure of human adenylate kinase 3, AK3, in complex with inhibitor Gp5A== | ||
<StructureSection load='6zjb' size='340' side='right'caption='[[6zjb]]' scene=''> | <StructureSection load='6zjb' size='340' side='right'caption='[[6zjb]], [[Resolution|resolution]] 1.82Å' 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=6ZJB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZJB FirstGlance]. <br> | <table><tr><td colspan='2'>[[6zjb]] is a 6 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=6ZJB OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=6ZJB FirstGlance]. <br> | ||
</td></tr><tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zjb OCA], [http://pdbe.org/6zjb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zjb RCSB], [http://www.ebi.ac.uk/pdbsum/6zjb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zjb 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=G5P:P1-(5-ADENOSYL)-P5-(5-GUANOSYL)+PENTAPHOSPHATE'>G5P</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr> | ||
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">AK3, AK3L1, AK6, AKL3L ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr> | |||
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Nucleoside-triphosphate--adenylate_kinase Nucleoside-triphosphate--adenylate kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.4.10 2.7.4.10] </span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=6zjb FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6zjb OCA], [http://pdbe.org/6zjb PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6zjb RCSB], [http://www.ebi.ac.uk/pdbsum/6zjb PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6zjb ProSAT]</span></td></tr> | |||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
ATP and GTP are exceptionally important molecules in biology with multiple, and often discrete, functions. Therefore, enzymes that bind to either of them must develop robust mechanisms to selectively utilize one or the other. Here, this specific problem is addressed by molecular studies of the human NMP kinase AK3, which uses GTP to phosphorylate AMP. AK3 plays an important role in the citric acid cycle, where it is responsible for GTP/GDP recycling. By combining a structural biology approach with functional experiments, we present a comprehensive structural and mechanistic understanding of the enzyme. We discovered that AK3 functions by recruitment of GTP to the active site, while ATP is rejected and nonproductively bound to the AMP binding site. Consequently, ATP acts as an inhibitor with respect to GTP and AMP. The overall features with specific recognition of the correct substrate and nonproductive binding by the incorrect substrate bear a strong similarity to previous findings for the ATP specific NMP kinase adenylate kinase. Taken together, we are now able to provide the fundamental principles for GTP and ATP selectivity in the large NMP kinase family. As a side-result originating from nonlinearity of chemical shifts in GTP and ATP titrations, we find that protein surfaces offer a general and weak binding affinity for both GTP and ATP. These nonspecific interactions likely act to lower the available intracellular GTP and ATP concentrations and may have driven evolution of the Michaelis constants of NMP kinases accordingly. | |||
Structural Basis for GTP versus ATP Selectivity in the NMP Kinase AK3.,Rogne P, Dulko-Smith B, Goodman J, Rosselin M, Grundstrom C, Hedberg C, Nam K, Sauer-Eriksson AE, Wolf-Watz M Biochemistry. 2020 Sep 11. doi: 10.1021/acs.biochem.0c00549. PMID:32822537<ref>PMID:32822537</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6zjb" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Human]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Grundstrom C]] | [[Category: Nucleoside-triphosphate--adenylate kinase]] | ||
[[Category: Rogne P]] | [[Category: Grundstrom, C]] | ||
[[Category: Sauer-Eriksson | [[Category: Rogne, P]] | ||
[[Category: Wolf-Watz M]] | [[Category: Sauer-Eriksson, A E]] | ||
[[Category: Wolf-Watz, M]] | |||
[[Category: Gp5a]] | |||
[[Category: Gtp:amp phosphotransferase]] | |||
[[Category: Transferase]] | |||
Revision as of 09:42, 7 October 2020
Crystal structure of human adenylate kinase 3, AK3, in complex with inhibitor Gp5ACrystal structure of human adenylate kinase 3, AK3, in complex with inhibitor Gp5A
Structural highlights
Publication Abstract from PubMedATP and GTP are exceptionally important molecules in biology with multiple, and often discrete, functions. Therefore, enzymes that bind to either of them must develop robust mechanisms to selectively utilize one or the other. Here, this specific problem is addressed by molecular studies of the human NMP kinase AK3, which uses GTP to phosphorylate AMP. AK3 plays an important role in the citric acid cycle, where it is responsible for GTP/GDP recycling. By combining a structural biology approach with functional experiments, we present a comprehensive structural and mechanistic understanding of the enzyme. We discovered that AK3 functions by recruitment of GTP to the active site, while ATP is rejected and nonproductively bound to the AMP binding site. Consequently, ATP acts as an inhibitor with respect to GTP and AMP. The overall features with specific recognition of the correct substrate and nonproductive binding by the incorrect substrate bear a strong similarity to previous findings for the ATP specific NMP kinase adenylate kinase. Taken together, we are now able to provide the fundamental principles for GTP and ATP selectivity in the large NMP kinase family. As a side-result originating from nonlinearity of chemical shifts in GTP and ATP titrations, we find that protein surfaces offer a general and weak binding affinity for both GTP and ATP. These nonspecific interactions likely act to lower the available intracellular GTP and ATP concentrations and may have driven evolution of the Michaelis constants of NMP kinases accordingly. Structural Basis for GTP versus ATP Selectivity in the NMP Kinase AK3.,Rogne P, Dulko-Smith B, Goodman J, Rosselin M, Grundstrom C, Hedberg C, Nam K, Sauer-Eriksson AE, Wolf-Watz M Biochemistry. 2020 Sep 11. doi: 10.1021/acs.biochem.0c00549. PMID:32822537[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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