3r9a

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{{STRUCTURE_3r9a| PDB=3r9a | SCENE= }}
 
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===Human alanine-glyoxylate aminotransferase in complex with the TPR domain of human PEX5P===
 
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{{ABSTRACT_PUBMED_22529745}}
 
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==Disease==
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==Human alanine-glyoxylate aminotransferase in complex with the TPR domain of human PEX5P==
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[[http://www.uniprot.org/uniprot/SPYA_HUMAN SPYA_HUMAN]] Defects in AGXT are the cause of hyperoxaluria primary type 1 (HP1) [MIM:[http://omim.org/entry/259900 259900]]; also known as primary hyperoxaluria type I (PH1) and oxalosis I. HP1 is a rare autosomal recessive inborn error of glyoxylate metabolism characterized by increased excretion of oxalate and glycolate, and the progressive accumulation of insoluble calcium oxalate in the kidney and urinary tract.<ref>PMID:1703535</ref><ref>PMID:2039493</ref><ref>PMID:1349575</ref><ref>PMID:1301173</ref><ref>PMID:8101040</ref><ref>PMID:9192270</ref><ref>PMID:9604803</ref><ref>PMID:10394939</ref><ref>PMID:10453743</ref><ref>PMID:10541294</ref><ref>PMID:10862087</ref><ref>PMID:10960483</ref><ref>PMID:12559847</ref><ref>PMID:12777626</ref><ref>PMID:15253729</ref><ref>PMID:15849466</ref><ref>PMID:15961946</ref><ref>PMID:15963748</ref> [[http://www.uniprot.org/uniprot/PEX5_HUMAN PEX5_HUMAN]] Defects in PEX5 are the cause of peroxisome biogenesis disorder 2A (PBD2A) [MIM:[http://omim.org/entry/214110 214110]]. A fatal peroxisome biogenesis disorder belonging to the Zellweger disease spectrum and characterized clinically by severe neurologic dysfunction with profound psychomotor retardation, severe hypotonia and neonatal seizures, craniofacial abnormalities, liver dysfunction, and biochemically by the absence of peroxisomes. Additional features include cardiovascular and skeletal defects, renal cysts, ocular abnormalities, and hearing impairment. Most severely affected individuals with the classic form of the disease (classic Zellweger syndrome) die within the first year of life.<ref>PMID:7719337</ref> Defects in PEX5 are the cause of peroxisome biogenesis disorder 2B (PBD2B) [MIM:[http://omim.org/entry/202370 202370]]. A peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.
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<StructureSection load='3r9a' size='340' side='right'caption='[[3r9a]], [[Resolution|resolution]] 2.35&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[3r9a]] 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=3R9A OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3R9A FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.35&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=LLP:(2S)-2-AMINO-6-[[3-HYDROXY-2-METHYL-5-(PHOSPHONOOXYMETHYL)PYRIDIN-4-YL]METHYLIDENEAMINO]HEXANOIC+ACID'>LLP</scene></td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3r9a FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3r9a OCA], [https://pdbe.org/3r9a PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3r9a RCSB], [https://www.ebi.ac.uk/pdbsum/3r9a PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3r9a ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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.
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== Function ==
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[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:23229545, PubMed:24055001, 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>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Alanine-glyoxylate aminotransferase is a peroxisomal enzyme, of which various missense mutations lead to irreversible kidney damage via primary hyperoxaluria type 1, in part caused by improper peroxisomal targeting. To unravel the molecular mechanism of its recognition by the peroxisomal receptor Pex5p, we have determined the crystal structure of the respective cargo-receptor complex. It shows an extensive protein/protein interface, with contributions from residues of the peroxisomal targeting signal 1 and additional loops of the C-terminal domain of the cargo. Sequence segments that are crucial for receptor recognition and hydrophobic core interactions within alanine-glyoxylate aminotransferase are overlapping, explaining why receptor recognition highly depends on a properly folded protein. We subsequently characterized several enzyme variants in vitro and in vivo and show that even minor protein fold perturbations are sufficient to impair Pex5p receptor recognition. We discuss how the knowledge of the molecular parameters for alanine-glyoxylate aminotransferase required for peroxisomal translocation could become useful for improved hyperoxaluria type 1 treatment.
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==Function==
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Molecular requirements for peroxisomal targeting of alanine-glyoxylate aminotransferase as an essential determinant in primary hyperoxaluria type 1.,Fodor K, Wolf J, Erdmann R, Schliebs W, Wilmanns M PLoS Biol. 2012 Apr;10(4):e1001309. Epub 2012 Apr 17. PMID:22529745<ref>PMID:22529745</ref>
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[[http://www.uniprot.org/uniprot/PEX5_HUMAN PEX5_HUMAN]] Binds to the C-terminal PTS1-type tripeptide peroxisomal targeting signal (SKL-type) and plays an essential role in peroxisomal protein import.<ref>PMID:7719337</ref><ref>PMID:7790377</ref><ref>PMID:7706321</ref>
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==About this Structure==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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[[3r9a]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. This structure supersedes the now removed PDB entry [http://oca.weizmann.ac.il/oca-bin/send-pdb?obs=1&id=3imz 3imz]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3R9A OCA].
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</div>
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<div class="pdbe-citations 3r9a" style="background-color:#fffaf0;"></div>
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==Reference==
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==See Also==
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<ref group="xtra">PMID:022529745</ref><references group="xtra"/><references/>
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*[[Aminotransferase 3D structures|Aminotransferase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Fodor, K.]]
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[[Category: Large Structures]]
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[[Category: Wilmanns, M.]]
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[[Category: Fodor K]]
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[[Category: Aminotransf pyruvate]]
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[[Category: Wilmanns M]]
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[[Category: Disease mutation]]
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[[Category: Membrane]]
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[[Category: Mitochondrion]]
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[[Category: Peroxiso biogenesis disorder]]
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[[Category: Peroxisome]]
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[[Category: Protein transport]]
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[[Category: Protein-protein complex]]
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[[Category: Pyridoxal phosphate]]
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[[Category: Tpr repeat]]
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[[Category: Tpr-domain]]
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[[Category: Transferase]]
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[[Category: Transferase-transport protein complex]]
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[[Category: Transpo zellweger syndrome]]
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Current revision

Human alanine-glyoxylate aminotransferase in complex with the TPR domain of human PEX5P

PDB ID 3r9a

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