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7s4c

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Crystal Structure of Inhibitor-bound Galactokinase

Structural highlights

7s4c is a 2 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 2.2Å
Ligands:	, , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

GALK1_HUMAN Defects in GALK1 are the cause of galactosemia II (GALCT2) [MIM:230200. Galactosemia II is an autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses.^[1] ^[2] ^[3] ^[4] ^[5] ^[6]

Function

GALK1_HUMAN Major enzyme for galactose metabolism.

Publication Abstract from PubMed

Classic galactosemia is a rare disease caused by inherited deficiency of galactose-1 phosphate uridylyltransferase (GALT). Accumulation of galactose-1 phosphate (gal-1P) is thought to be the major cause of the chronic complications associated with this disease, which currently has no treatment. Inhibiting galactokinase (GALK1), the enzyme that generates galactose-1 phosphate, has been proposed as a novel strategy for treating classic galactosemia. Our previous work identified a highly selective unique dihydropyrimidine inhibitor against GALK1. With the determination of a co-crystal structure of this inhibitor with human GALK1, we initiated a structure-based structure-activity relationship (SAR) optimization campaign that yielded novel analogs with potent biochemical inhibition (IC50 < 100 nM). Lead compounds were also able to prevent gal-1P accumulation in patient-derived cells at low micromolar concentrations and have pharmacokinetic properties suitable for evaluation in rodent models of galactosemia.

Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors.,Liu L, Tang M, Pragani R, Whitby FG, Zhang YQ, Balakrishnan B, Fang Y, Karavadhi S, Tao D, LeClair CA, Hall MD, Marugan JJ, Boxer M, Shen M, Hill CP, Lai K, Patnaik S J Med Chem. 2021 Sep 23;64(18):13551-13571. doi: 10.1021/acs.jmedchem.1c00945., Epub 2021 Sep 7. PMID:34491744^[7]

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

References

↑ Kalaydjieva L, Perez-Lezaun A, Angelicheva D, Onengut S, Dye D, Bosshard NU, Jordanova A, Savov A, Yanakiev P, Kremensky I, Radeva B, Hallmayer J, Markov A, Nedkova V, Tournev I, Aneva L, Gitzelmann R. A founder mutation in the GK1 gene is responsible for galactokinase deficiency in Roma (Gypsies). Am J Hum Genet. 1999 Nov;65(5):1299-307. PMID:10521295 doi:S0002-9297(07)62136-3
↑ Kolosha V, Anoia E, de Cespedes C, Gitzelmann R, Shih L, Casco T, Saborio M, Trejos R, Buist N, Tedesco T, Skach W, Mitelmann O, Ledee D, Huang K, Stambolian D. Novel mutations in 13 probands with galactokinase deficiency. Hum Mutat. 2000;15(5):447-53. PMID:10790206 doi:<447::AID-HUMU6>3.0.CO;2-M 10.1002/(SICI)1098-1004(200005)15:5<447::AID-HUMU6>3.0.CO;2-M
↑ Okano Y, Asada M, Fujimoto A, Ohtake A, Murayama K, Hsiao KJ, Choeh K, Yang Y, Cao Q, Reichardt JK, Niihira S, Imamura T, Yamano T. A genetic factor for age-related cataract: identification and characterization of a novel galactokinase variant, "Osaka," in Asians. Am J Hum Genet. 2001 Apr;68(4):1036-42. Epub 2001 Feb 23. PMID:11231902 doi:S0002-9297(07)61428-1
↑ Hunter M, Angelicheva D, Levy HL, Pueschel SM, Kalaydjieva L. Novel mutations in the GALK1 gene in patients with galactokinase deficiency. Hum Mutat. 2001;17(1):77-8. PMID:11139256 doi:<77::AID-HUMU20>3.0.CO;2-H 10.1002/1098-1004(2001)17:1<77::AID-HUMU20>3.0.CO;2-H
↑ Timson DJ, Reece RJ. Functional analysis of disease-causing mutations in human galactokinase. Eur J Biochem. 2003 Apr;270(8):1767-74. PMID:12694189
↑ Sangiuolo F, Magnani M, Stambolian D, Novelli G. Biochemical characterization of two GALK1 mutations in patients with galactokinase deficiency. Hum Mutat. 2004 Apr;23(4):396. PMID:15024738 doi:10.1002/humu.9223
↑ Liu L, Tang M, Pragani R, Whitby FG, Zhang YQ, Balakrishnan B, Fang Y, Karavadhi S, Tao D, LeClair CA, Hall MD, Marugan JJ, Boxer M, Shen M, Hill CP, Lai K, Patnaik S. Structure-Based Optimization of Small Molecule Human Galactokinase Inhibitors. J Med Chem. 2021 Sep 23;64(18):13551-13571. doi: 10.1021/acs.jmedchem.1c00945., Epub 2021 Sep 7. PMID:34491744 doi:http://dx.doi.org/10.1021/acs.jmedchem.1c00945

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7s4c"

Categories: Homo sapiens | Large Structures | Whitby FG

@@ Line 3: / Line 3: @@
 <StructureSection load='7s4c' size='340' side='right'caption='[[7s4c]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[7s4c]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7S4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S4C FirstGlance]. <br>
+<table><tr><td colspan='2'>[[7s4c]] is a 2 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=7S4C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7S4C FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLA:ALPHA+D-GALACTOSE'>GLA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=V3V:2-({(4R)-4-(2-chlorophenyl)-2-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-6-methyl-1,4-dihydropyrimidine-5-carbonyl}amino)pyridine-4-carboxylic+acid'>V3V</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]] 2.2&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[7s49|7s49]], [[7rcm|7rcm]], [[7rcl|7rcl]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GLA:ALPHA+D-GALACTOSE'>GLA</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=V3V:2-({(4R)-4-(2-chlorophenyl)-2-[(6-fluoro-1,3-benzoxazol-2-yl)amino]-6-methyl-1,4-dihydropyrimidine-5-carbonyl}amino)pyridine-4-carboxylic+acid'>V3V</scene></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Galactokinase Galactokinase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.1.6 2.7.1.6] </span></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=7s4c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7s4c OCA], [https://pdbe.org/7s4c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7s4c RCSB], [https://www.ebi.ac.uk/pdbsum/7s4c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7s4c ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Defects in GALK1 are the cause of galactosemia II (GALCT2) [MIM:[https://omim.org/entry/230200 230200]]. Galactosemia II is an autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses.<ref>PMID:10521295</ref> <ref>PMID:10790206</ref> <ref>PMID:11231902</ref> <ref>PMID:11139256</ref> <ref>PMID:12694189</ref> <ref>PMID:15024738</ref>
+[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN] Defects in GALK1 are the cause of galactosemia II (GALCT2) [MIM:[https://omim.org/entry/230200 230200]. Galactosemia II is an autosomal recessive deficiency characterized by congenital cataracts during infancy and presenile cataracts in the adult population. The cataracts are secondary to accumulation of galactitol in the lenses.<ref>PMID:10521295</ref> <ref>PMID:10790206</ref> <ref>PMID:11231902</ref> <ref>PMID:11139256</ref> <ref>PMID:12694189</ref> <ref>PMID:15024738</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Major enzyme for galactose metabolism.
+[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN] Major enzyme for galactose metabolism.
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 22: / Line 21: @@
 </div>
 <div class="pdbe-citations 7s4c" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Galactokinase|Galactokinase]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Galactokinase]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Whitby, F G]]
+[[Category: Whitby FG]]
-[[Category: Disulfide]]
-[[Category: Galactose]]
-[[Category: Galk]]
-[[Category: Inhibitor]]
-[[Category: Sugar binding protein]]
-[[Category: Transferase-inhibitor complex]]

7s4c

From Proteopedia

Current revision

Crystal Structure of Inhibitor-bound Galactokinase

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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