6dqg

From Proteopedia

(Difference between revisions)

Revision as of 06:46, 9 January 2019

Human glutamate dehydrogenase, H454Y mutant

Structural highlights

6dqg is a 6 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Gene:	GLUD1, GLUD (HUMAN)
Activity:	Glutamate dehydrogenase (NAD(P)(+)), with EC number 1.4.1.3
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

[DHE3_HUMAN] Defects in GLUD1 are the cause of familial hyperinsulinemic hypoglycemia type 6 (HHF6) [MIM:606762]; also known as hyperinsulinism-hyperammonemia syndrome (HHS). Familial hyperinsulinemic hypoglycemia [MIM:256450], also referred to as congenital hyperinsulinism, nesidioblastosis, or persistent hyperinsulinemic hypoglycemia of infancy (PPHI), is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. In HHF6 elevated oxidation rate of glutamate to alpha-ketoglutarate stimulates insulin secretion in the pancreatic beta cells, while they impair detoxification of ammonium in the liver.^[1] ^[2] ^[3] ^[4]

Function

[DHE3_HUMAN] May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity).

Publication Abstract from PubMed

Mammalian glutamate dehydrogenase (GDH) has complex allosteric regulation and the loss of GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS) where insulin is hypersecreted upon consumption of protein. The archetypical HHS lesion is H454Y and lies in the GTP binding pocket. To better understand the mechanism of HHS, we determined the crystal structure of H454Y. When the bovine GDH crystal structures were minimized to prepare for further computational analysis, unusually large deviations were found at the allosteric NADH binding site due to chemical sequence errors. Notably, 387 lies in an allosteric where several activators and inhibitors bind and should be lysine rather than asparagine. All structures were re-refined and the consequence of this sequence error on NADH binding was calculated using free energy perturbation. The binding free energy penalty going from the correct to incorrect sequence found is +5 kcal/mol per site and therefore has a significant impact on drug development. BROADER AUDIENCE ABSTRACT: Glutamate dehydrogenase is a key enzyme involved in amino acid catabolism. As such, it is heavily regulated in animals by a wide array of metabolites. The importance of this regulation is most apparent in a genetic disorder called hyperinsulinism/hyperammonemia (HHS) where patients hypersecrete insulin upon the consumption of protein. We determined the atomic structure of one of these HHS mutants to better understand the disease and also analyzed an allosteric regulatory site.

Glutamate dehydrogenase: Structure of a hyperinsulinism mutant, corrections to the atomic model, and insights into a regulatory site.,Nassar OM, Li C, Stanley CA, Pettitt BM, Smith TJ Proteins. 2019 Jan;87(1):41-50. doi: 10.1002/prot.25620. Epub 2018 Nov 18. PMID:30367518^[5]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Stanley CA, Lieu YK, Hsu BY, Burlina AB, Greenberg CR, Hopwood NJ, Perlman K, Rich BH, Zammarchi E, Poncz M. Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene. N Engl J Med. 1998 May 7;338(19):1352-7. PMID:9571255
↑ Miki Y, Taki T, Ohura T, Kato H, Yanagisawa M, Hayashi Y. Novel missense mutations in the glutamate dehydrogenase gene in the congenital hyperinsulinism-hyperammonemia syndrome. J Pediatr. 2000 Jan;136(1):69-72. PMID:10636977
↑ Santer R, Kinner M, Passarge M, Superti-Furga A, Mayatepek E, Meissner T, Schneppenheim R, Schaub J. Novel missense mutations outside the allosteric domain of glutamate dehydrogenase are prevalent in European patients with the congenital hyperinsulinism-hyperammonemia syndrome. Hum Genet. 2001 Jan;108(1):66-71. PMID:11214910
↑ MacMullen C, Fang J, Hsu BY, Kelly A, de Lonlay-Debeney P, Saudubray JM, Ganguly A, Smith TJ, Stanley CA. Hyperinsulinism/hyperammonemia syndrome in children with regulatory mutations in the inhibitory guanosine triphosphate-binding domain of glutamate dehydrogenase. J Clin Endocrinol Metab. 2001 Apr;86(4):1782-7. PMID:11297618
↑ Nassar OM, Li C, Stanley CA, Pettitt BM, Smith TJ. Glutamate dehydrogenase: Structure of a hyperinsulinism mutant, corrections to the atomic model, and insights into a regulatory site. Proteins. 2019 Jan;87(1):41-50. doi: 10.1002/prot.25620. Epub 2018 Nov 18. PMID:30367518 doi:http://dx.doi.org/10.1002/prot.25620

1 Structural highlights
2 Disease
3 Function
4 Publication Abstract from PubMed
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6dqg"

@@ Line 3: / Line 3: @@
 <StructureSection load='6dqg' size='340' side='right' caption='[[6dqg]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6dqg]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DQG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DQG FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6dqg]] 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=6DQG OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6DQG FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GLUD1, GLUD ([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/Glutamate_dehydrogenase_(NAD(P)(+)) Glutamate dehydrogenase (NAD(P)(+))], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=1.4.1.3 1.4.1.3] </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=6dqg FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dqg OCA], [http://pdbe.org/6dqg PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6dqg RCSB], [http://www.ebi.ac.uk/pdbsum/6dqg PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6dqg ProSAT]</span></td></tr>
@@ Line 12: / Line 13: @@
 == Function ==
 [[http://www.uniprot.org/uniprot/DHE3_HUMAN DHE3_HUMAN]] May be involved in learning and memory reactions by increasing the turnover of the excitatory neurotransmitter glutamate (By similarity).
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Mammalian glutamate dehydrogenase (GDH) has complex allosteric regulation and the loss of GTP inhibition causes the hyperinsulinism/hyperammonemia syndrome (HHS) where insulin is hypersecreted upon consumption of protein. The archetypical HHS lesion is H454Y and lies in the GTP binding pocket. To better understand the mechanism of HHS, we determined the crystal structure of H454Y. When the bovine GDH crystal structures were minimized to prepare for further computational analysis, unusually large deviations were found at the allosteric NADH binding site due to chemical sequence errors. Notably, 387 lies in an allosteric where several activators and inhibitors bind and should be lysine rather than asparagine. All structures were re-refined and the consequence of this sequence error on NADH binding was calculated using free energy perturbation. The binding free energy penalty going from the correct to incorrect sequence found is +5 kcal/mol per site and therefore has a significant impact on drug development. BROADER AUDIENCE ABSTRACT: Glutamate dehydrogenase is a key enzyme involved in amino acid catabolism. As such, it is heavily regulated in animals by a wide array of metabolites. The importance of this regulation is most apparent in a genetic disorder called hyperinsulinism/hyperammonemia (HHS) where patients hypersecrete insulin upon the consumption of protein. We determined the atomic structure of one of these HHS mutants to better understand the disease and also analyzed an allosteric regulatory site.
+Glutamate dehydrogenase: Structure of a hyperinsulinism mutant, corrections to the atomic model, and insights into a regulatory site.,Nassar OM, Li C, Stanley CA, Pettitt BM, Smith TJ Proteins. 2019 Jan;87(1):41-50. doi: 10.1002/prot.25620. Epub 2018 Nov 18. PMID:30367518<ref>PMID:30367518</ref>
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+</div>
+<div class="pdbe-citations 6dqg" style="background-color:#fffaf0;"></div>
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Smith, T J]]
 [[Category: Dehydrogenase]]

6dqg

From Proteopedia

Revision as of 06:46, 9 January 2019

Human glutamate dehydrogenase, H454Y mutant

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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