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==Human glucokinase in complex with novel pyrazole activator.==
==Human glucokinase in complex with novel pyrazole activator.==
<StructureSection load='5v4x' size='340' side='right' caption='[[5v4x]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
<StructureSection load='5v4x' size='340' side='right'caption='[[5v4x]], [[Resolution|resolution]] 2.08&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[5v4x]] is a 1 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=5V4X OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5V4X FirstGlance]. <br>
<table><tr><td colspan='2'>[[5v4x]] is a 1 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=5V4X OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5V4X FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=8WJ:(2S)-3-cyclohexyl-2-[4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(1,3-thiazol-2-yl)propanamide'>8WJ</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></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]] 2.08&#8491;</td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5v4w|5v4w]]</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=8WJ:(2S)-3-cyclohexyl-2-[4-(cyclopentylsulfonyl)-2-oxopyridin-1(2H)-yl]-N-(1,3-thiazol-2-yl)propanamide'>8WJ</scene>, <scene name='pdbligand=GLC:ALPHA-D-GLUCOSE'>GLC</scene>, <scene name='pdbligand=IOD:IODIDE+ION'>IOD</scene></td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">GCK ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</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=5v4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v4x OCA], [https://pdbe.org/5v4x PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5v4x RCSB], [https://www.ebi.ac.uk/pdbsum/5v4x PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5v4x ProSAT]</span></td></tr>
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Glucokinase Glucokinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.2 2.7.1.2] </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=5v4x FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5v4x OCA], [http://pdbe.org/5v4x PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5v4x RCSB], [http://www.ebi.ac.uk/pdbsum/5v4x PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5v4x ProSAT]</span></td></tr>
</table>
</table>
== Disease ==
== Disease ==
[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[http://omim.org/entry/125851 125851]]; also shortened MODY-2. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref>  Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[http://omim.org/entry/602485 602485]]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>
[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN] Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:[https://omim.org/entry/125851 125851]; also shortened MODY-2. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.<ref>PMID:1502186</ref> <ref>PMID:1464666</ref> <ref>PMID:1303265</ref> <ref>PMID:8495817</ref> <ref>PMID:8325892</ref> <ref>PMID:8446612</ref> <ref>PMID:8168652</ref> <ref>PMID:9049484</ref> <ref>PMID:10694920</ref> <ref>PMID:9662401</ref> <ref>PMID:10588527</ref> <ref>PMID:11106831</ref> <ref>PMID:11372010</ref>  Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:[https://omim.org/entry/602485 602485]; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.<ref>PMID:9435328</ref>  
== Function ==
== Function ==
[[http://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN]] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
[https://www.uniprot.org/uniprot/HXK4_HUMAN HXK4_HUMAN] Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Guided by co-crystal structural information obtained from a different series we were exploring, a scaffold morphing and SBDD approach led to the discovery of the 1,4-disubstituted indazole series as a novel class of GKAs that potently activate GK in enzyme and cell assays. anti-diabetic OGTT efficacy was demonstrated with 29 in a rodent models of type 2 diabetes.


Discovery of potent and orally active 1,4-disubstituted indazoles as novel allosteric glucokinase activators.,Cheruvallath ZS, Gwaltney SL 2nd, Sabat M, Tang M, Wang H, Jennings A, Hosfield D, Lee B, Wu Y, Halkowycz P, Grimshaw CE Bioorg Med Chem Lett. 2017 Jun 15;27(12):2678-2682. doi:, 10.1016/j.bmcl.2017.04.041. Epub 2017 Apr 13. PMID:28512030<ref>PMID:28512030</ref>
==See Also==
 
*[[Hexokinase 3D structures|Hexokinase 3D structures]]
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 5v4x" style="background-color:#fffaf0;"></div>
== References ==
== References ==
<references/>
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Glucokinase]]
[[Category: Homo sapiens]]
[[Category: Human]]
[[Category: Large Structures]]
[[Category: Hosfiled, D J]]
[[Category: Hosfiled DJ]]
[[Category: Skene, R J]]
[[Category: Skene RJ]]
[[Category: Activator]]
[[Category: Complex]]
[[Category: Transferase-transferase activator complex]]

Latest revision as of 17:31, 6 March 2024

Human glucokinase in complex with novel pyrazole activator.Human glucokinase in complex with novel pyrazole activator.

Structural highlights

5v4x is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 2.08Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

HXK4_HUMAN Defects in GCK are the cause of maturity-onset diabetes of the young type 2 (MODY2) [MIM:125851; also shortened MODY-2. MODY is a form of diabetes that is characterized by an autosomal dominant mode of inheritance, onset in childhood or early adulthood (usually before 25 years of age), a primary defect in insulin secretion and frequent insulin-independence at the beginning of the disease.[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] Defects in GCK are the cause of familial hyperinsulinemic hypoglycemia type 3 (HHF3) [MIM:602485; also known as persistent hyperinsulinemic hypoglycemia of infancy (PHHI) or congenital hyperinsulinism. HHF is the most common cause of persistent hypoglycemia in infancy. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur.[14]

Function

HXK4_HUMAN Catalyzes the initial step in utilization of glucose by the beta-cell and liver at physiological glucose concentration. Glucokinase has a high Km for glucose, and so it is effective only when glucose is abundant. The role of GCK is to provide G6P for the synthesis of glycogen. Pancreatic glucokinase plays an important role in modulating insulin secretion. Hepatic glucokinase helps to facilitate the uptake and conversion of glucose by acting as an insulin-sensitive determinant of hepatic glucose usage.

See Also

References

  1. ↑ Stoffel M, Froguel P, Takeda J, Zouali H, Vionnet N, Nishi S, Weber IT, Harrison RW, Pilkis SJ, Lesage S, et al.. Human glucokinase gene: isolation, characterization, and identification of two missense mutations linked to early-onset non-insulin-dependent (type 2) diabetes mellitus. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7698-702. PMID:1502186
  2. ↑ Sakura H, Eto K, Kadowaki H, Simokawa K, Ueno H, Koda N, Fukushima Y, Akanuma Y, Yazaki Y, Kadowaki T. Structure of the human glucokinase gene and identification of a missense mutation in a Japanese patient with early-onset non-insulin-dependent diabetes mellitus. J Clin Endocrinol Metab. 1992 Dec;75(6):1571-3. PMID:1464666
  3. ↑ Stoffel M, Patel P, Lo YM, Hattersley AT, Lucassen AM, Page R, Bell JI, Bell GI, Turner RC, Wainscoat JS. Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes. Nat Genet. 1992 Oct;2(2):153-6. PMID:1303265 doi:http://dx.doi.org/10.1038/ng1092-153
  4. ↑ Stoffel M, Bell KL, Blackburn CL, Powell KL, Seo TS, Takeda J, Vionnet N, Xiang KS, Gidh-Jain M, Pilkis SJ, et al.. Identification of glucokinase mutations in subjects with gestational diabetes mellitus. Diabetes. 1993 Jun;42(6):937-40. PMID:8495817
  5. ↑ Takeda J, Gidh-Jain M, Xu LZ, Froguel P, Velho G, Vaxillaire M, Cohen D, Shimada F, Makino H, Nishi S, et al.. Structure/function studies of human beta-cell glucokinase. Enzymatic properties of a sequence polymorphism, mutations associated with diabetes, and other site-directed mutants. J Biol Chem. 1993 Jul 15;268(20):15200-4. PMID:8325892
  6. ↑ Gidh-Jain M, Takeda J, Xu LZ, Lange AJ, Vionnet N, Stoffel M, Froguel P, Velho G, Sun F, Cohen D, et al.. Glucokinase mutations associated with non-insulin-dependent (type 2) diabetes mellitus have decreased enzymatic activity: implications for structure/function relationships. Proc Natl Acad Sci U S A. 1993 Mar 1;90(5):1932-6. PMID:8446612
  7. ↑ Hager J, Blanche H, Sun F, Vaxillaire NV, Poller W, Cohen D, Czernichow P, Velho G, Robert JJ, Cohen N, et al.. Six mutations in the glucokinase gene identified in MODY by using a nonradioactive sensitive screening technique. Diabetes. 1994 May;43(5):730-3. PMID:8168652
  8. ↑ Velho G, Blanche H, Vaxillaire M, Bellanne-Chantelot C, Pardini VC, Timsit J, Passa P, Deschamps I, Robert JJ, Weber IT, Marotta D, Pilkis SJ, Lipkind GM, Bell GI, Froguel P. Identification of 14 new glucokinase mutations and description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997 Feb;40(2):217-24. PMID:9049484 doi:10.1007/s001250050666
  9. ↑ Guazzini B, Gaffi D, Mainieri D, Multari G, Cordera R, Bertolini S, Pozza G, Meschi F, Barbetti F. Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. Hum Mutat. 1998;12(2):136. PMID:10694920 doi:<136::AID-HUMU11>3.0.CO;2-0 10.1002/(SICI)1098-1004(1998)12:2<136::AID-HUMU11>3.0.CO;2-0
  10. ↑ Hattersley AT, Beards F, Ballantyne E, Appleton M, Harvey R, Ellard S. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998 Jul;19(3):268-70. PMID:9662401 doi:10.1038/953
  11. ↑ Ng MC, Cockburn BN, Lindner TH, Yeung VT, Chow CC, So WY, Li JK, Lo YM, Lee ZS, Cockram CS, Critchley JA, Bell GI, Chan JC. Molecular genetics of diabetes mellitus in Chinese subjects: identification of mutations in glucokinase and hepatocyte nuclear factor-1alpha genes in patients with early-onset type 2 diabetes mellitus/MODY. Diabet Med. 1999 Nov;16(11):956-63. PMID:10588527
  12. ↑ Nam JH, Lee HC, Kim YH, Cha BS, Song YD, Lim SK, Kim KR, Huh KB. Identification of glucokinase mutation in subjects with post-renal transplantation diabetes mellitus. Diabetes Res Clin Pract. 2000 Dec;50(3):169-76. PMID:11106831
  13. ↑ Njolstad PR, Sovik O, Cuesta-Munoz A, Bjorkhaug L, Massa O, Barbetti F, Undlien DE, Shiota C, Magnuson MA, Molven A, Matschinsky FM, Bell GI. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001 May 24;344(21):1588-92. PMID:11372010 doi:10.1056/NEJM200105243442104
  14. ↑ Glaser B, Kesavan P, Heyman M, Davis E, Cuesta A, Buchs A, Stanley CA, Thornton PS, Permutt MA, Matschinsky FM, Herold KC. Familial hyperinsulinism caused by an activating glucokinase mutation. N Engl J Med. 1998 Jan 22;338(4):226-30. PMID:9435328 doi:10.1056/NEJM199801223380404

5v4x, resolution 2.08Å

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