7ns7: Difference between revisions
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==Human L-alanine:glyoxylate aminotransferase minor allele variant: AGXT-Mi (P11L-I340M)== | ==Human L-alanine:glyoxylate aminotransferase minor allele variant: AGXT-Mi (P11L-I340M)== | ||
<StructureSection load='7ns7' size='340' side='right'caption='[[7ns7]]' scene=''> | <StructureSection load='7ns7' size='340' side='right'caption='[[7ns7]], [[Resolution|resolution]] 2.20Å' 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=7NS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NS7 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7ns7]] is a 2 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=7NS7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7NS7 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=7ns7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ns7 OCA], [https://pdbe.org/7ns7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ns7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ns7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ns7 ProSAT]</span></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]] 2.2Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</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=7ns7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7ns7 OCA], [https://pdbe.org/7ns7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7ns7 RCSB], [https://www.ebi.ac.uk/pdbsum/7ns7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7ns7 ProSAT]</span></td></tr> | |||
</table> | </table> | ||
== Disease == | |||
[https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Primary hyperoxaluria type 1. The disease is caused by variants affecting the gene represented in this entry. | |||
== Function == | |||
[https://www.uniprot.org/uniprot/AGT1_HUMAN AGT1_HUMAN] Peroxisomal aminotransferase that catalyzes the transamination of glyoxylate to glycine and contributes to the glyoxylate detoxification (PubMed:10960483, PubMed:12777626, PubMed:24055001, PubMed:23229545, PubMed:26149463). Also catalyzes the transamination between L-serine and pyruvate and contributes to gluconeogenesis from the L-serine metabolism (PubMed:10347152).<ref>PMID:10347152</ref> <ref>PMID:10960483</ref> <ref>PMID:12777626</ref> <ref>PMID:23229545</ref> <ref>PMID:24055001</ref> <ref>PMID:26149463</ref> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The conformational landscape of a protein is constantly expanded by genetic variations that have a minimal impact on the function(s) while causing subtle effects on protein structure. The wider the conformational space sampled by these variants, the higher the probabilities to adapt to changes in environmental conditions. However, the probability that a single mutation may result in a pathogenic phenotype also increases. Here we present a paradigmatic example of how protein evolution balances structural stability and dynamics to maximize protein adaptability and preserve protein fitness. We took advantage of known genetic variations of human alanine:glyoxylate aminotransferase (AGT1), which is present as a common major allelic form (AGT-Ma) and a minor polymorphic form (AGT-Mi) expressed in 20% of Caucasian population. By integrating crystallographic studies and molecular dynamics simulations, we show that AGT-Ma is endowed with structurally unstable (frustrated) regions, which become disordered in AGT-Mi. An in-depth biochemical characterization of variants from an anticonsensus library, encompassing the frustrated regions, correlates this plasticity to a fitness window defined by AGT-Ma and AGT-Mi. Finally, co-immunoprecipitation analysis suggests that structural frustration in AGT1 could favor additional functions related to protein-protein interactions. These results expand our understanding of protein structural evolution by establishing that naturally occurring genetic variations tip the balance between stability and frustration to maximize the ensemble of conformations falling within a well-defined fitness window, thus expanding the adaptability potential of the protein. | |||
Structural dynamics shape the fitness window of alanine:glyoxylate aminotransferase.,Dindo M, Pascarelli S, Chiasserini D, Grottelli S, Costantini C, Uechi GI, Giardina G, Laurino P, Cellini B Protein Sci. 2022 May;31(5):e4303. doi: 10.1002/pro.4303. PMID:35481644<ref>PMID:35481644</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 7ns7" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Cellini B]] | [[Category: Cellini B]] | ||
[[Category: Dindo M]] | [[Category: Dindo M]] | ||