4bzy

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Current revision (12:00, 20 December 2023) (edit) (undo)
 
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== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[4bzy]] is a 3 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=4BZY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZY FirstGlance]. <br>
<table><tr><td colspan='2'>[[4bzy]] is a 3 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=4BZY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4BZY FirstGlance]. <br>
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</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=4bzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzy OCA], [https://pdbe.org/4bzy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bzy RCSB], [https://www.ebi.ac.uk/pdbsum/4bzy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzy ProSAT]</span></td></tr>
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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]] 2.75&#8491;</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=4bzy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4bzy OCA], [https://pdbe.org/4bzy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4bzy RCSB], [https://www.ebi.ac.uk/pdbsum/4bzy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4bzy ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
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[[https://www.uniprot.org/uniprot/GLGB_HUMAN GLGB_HUMAN]] Adult polyglucosan body disease;Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form;Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form;Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form. The disease is caused by mutations affecting the gene represented in this entry. Neuromuscular perinatal glycogen storage disease type 4 is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. The disease is caused by mutations affecting the gene represented in this entry.
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[https://www.uniprot.org/uniprot/GLGB_HUMAN GLGB_HUMAN] Adult polyglucosan body disease;Glycogen storage disease due to glycogen branching enzyme deficiency, adult neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, non progressive hepatic form;Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, childhood combined hepatic and myopathic form;Glycogen storage disease due to glycogen branching enzyme deficiency, childhood neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, fatal perinatal neuromuscular form;Glycogen storage disease due to glycogen branching enzyme deficiency, progressive hepatic form. The disease is caused by mutations affecting the gene represented in this entry. Neuromuscular perinatal glycogen storage disease type 4 is associated with non-immune hydrops fetalis, a generalized edema of the fetus with fluid accumulation in the body cavities due to non-immune causes. Non-immune hydrops fetalis is not a diagnosis in itself but a symptom, a feature of many genetic disorders, and the end-stage of a wide variety of disorders. The disease is caused by mutations affecting the gene represented in this entry.
== Function ==
== Function ==
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[[https://www.uniprot.org/uniprot/GLGB_HUMAN GLGB_HUMAN]] Required for sufficient glycogen accumulation. The alpha 1-6 branches of glycogen play an important role in increasing the solubility of the molecule and, consequently, in reducing the osmotic pressure within cells.
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[https://www.uniprot.org/uniprot/GLGB_HUMAN GLGB_HUMAN] Required for sufficient glycogen accumulation. The alpha 1-6 branches of glycogen play an important role in increasing the solubility of the molecule and, consequently, in reducing the osmotic pressure within cells.
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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Glycogen branching enzyme 1 (GBE1) plays an essential role in glycogen biosynthesis by generating alpha-1,6-glucosidic branches from alpha-1,4-linked glucose chains, to increase solubility of the glycogen polymer. Mutations in the GBE1 gene lead to the heterogeneous early-onset glycogen storage disorder type IV (GSDIV) or the late-onset adult polyglucosan body disease (APBD). To better understand this essential enzyme, we crystallized human GBE1 in the apo form, and in complex with a tetra- or hepta-saccharide. The GBE1 structure reveals a conserved amylase core that houses the active center for the branching reaction, and harbors almost all GSDIV and APBD mutations. A non-catalytic binding cleft, proximal to the site of the common APBD mutation p.Y329S, was found to bind the tetra- and hepta-saccharides, and may represent a higher-affinity site employed to anchor the complex glycogen substrate for the branching reaction. Expression of recombinant GBE1-p.Y329S resulted in drastically-reduced protein yield and solubility compared to wild-type, suggesting this disease allele causes protein misfolding and may be amenable to small molecule stabilization. To explore this, we generated a structural model of GBE1-p.Y329S and designed peptides ab initio to stabilize the mutation. As proof-of-principle, we evaluated treatment of one tetra-peptide, Leu-Thr-Lys-Glu, in APBD patient cells. We demonstrate intracellular transport of this peptide, its binding and stabilization of GBE1-p.Y329S, and 2-fold increased mutant enzymatic activity compared to untreated patient cells. Together, our data provide the rationale and starting point for the screening of small molecule chaperones which could become novel therapies for this disease.
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Structural basis of glycogen branching enzyme deficiency and pharmacologic rescue by rational peptide design.,Froese DS, Michaeli A, McCorvie TJ, Krojer T, Sasi M, Melaev E, Goldblum A, Zatsepin M, Lossos A, Alvarez R, Escriba PV, Minaissan BA, von Delft F, Kakhlon O, Yue WW Hum Mol Genet. 2015 Jul 21. pii: ddv280. PMID:26199317<ref>PMID:26199317</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4bzy" style="background-color:#fffaf0;"></div>
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== References ==
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<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>

Current revision

Crystal structure of human glycogen branching enzyme (GBE1)

PDB ID 4bzy

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