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1nr1

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Revision as of 15:39, 12 October 2017

Crystal structure of the R463A mutant of human Glutamate dehydrogenase

Structural highlights

1nr1 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.
Related:	1l1f, 1nqt, 1nr7
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).

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Glutamate dehydrogenase (GDH) is found in all organisms and catalyzes the reversible oxidative deamination of L-glutamate to 2-oxoglutarate. Unlike GDH from bacteria, mammalian GDH exhibits negative cooperativity with respect to coenzyme, activation by ADP, and inhibition by GTP. Presented here are the structures of apo bovine GDH, bovine GDH complexed with ADP, and the R463A mutant form of human GDH (huGDH) that is insensitive to ADP activation. In the absence of active site ligands, the catalytic cleft is in the open conformation, and the hexamers form long polymers in the crystal cell with more interactions than found in the abortive complex crystals. This is consistent with the fact that ADP promotes aggregation in solution. ADP is shown to bind to the second, inhibitory, NADH site yet causes activation. The beta-phosphates of the bound ADP interact with R459 (R463 in huGDH) on the pivot helix. The structure of the ADP-resistant, R463A mutant of human GDH is identical to native GDH with the exception of the truncated side chain on the pivot helix. Together, these results strongly suggest that ADP activates by facilitating the opening of the catalytic cleft. From alignment of GDH from various sources, it is likely that the antenna evolved in the protista prior to the formation of purine regulatory sites. This suggests that there was some selective advantage of the antenna itself and that animals evolved new functions for GDH through the addition of allosteric regulation.

Structural studies on ADP activation of mammalian glutamate dehydrogenase and the evolution of regulation.,Banerjee S, Schmidt T, Fang J, Stanley CA, Smith TJ Biochemistry. 2003 Apr 1;42(12):3446-56. PMID:12653548^[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
↑ Banerjee S, Schmidt T, Fang J, Stanley CA, Smith TJ. Structural studies on ADP activation of mammalian glutamate dehydrogenase and the evolution of regulation. Biochemistry. 2003 Apr 1;42(12):3446-56. PMID:12653548 doi:http://dx.doi.org/10.1021/bi0206917

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/1nr1"

@@ Line 3: / Line 3: @@
 <StructureSection load='1nr1' size='340' side='right' caption='[[1nr1]], [[Resolution|resolution]] 3.30&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[1nr1]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1NR1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1NR1 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[1nr1]] 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=1NR1 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1NR1 FirstGlance]. <br>
 </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1l1f|1l1f]], [[1nqt|1nqt]], [[1nr7|1nr7]]</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>
@@ Line 31: / Line 31: @@
 </div>
 <div class="pdbe-citations 1nr1" style="background-color:#fffaf0;"></div>
-==See Also==
-*[[Glutamate dehydrogenase|Glutamate dehydrogenase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Human]]
 [[Category: Banerjee, S]]
 [[Category: Fang, J]]

1nr1

From Proteopedia

Revision as of 15:39, 12 October 2017

Crystal structure of the R463A mutant of human Glutamate dehydrogenase

Structural highlights

Disease

Function

Evolutionary Conservation

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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