7rcm: Difference between revisions

From Proteopedia
Jump to navigation Jump to search
← Older editNewer edit →
No edit summary
No edit summary
Line 1: Line 1:


==Crystal Structure of ADP-bound Galactokinase==
==Crystal Structure of ADP-bound Galactokinase==
<StructureSection load='7rcm' size='340' side='right'caption='[[7rcm]]' scene=''>
<StructureSection load='7rcm' size='340' side='right'caption='[[7rcm]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RCM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RCM FirstGlance]. <br>
<table><tr><td colspan='2'>[[7rcm]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7RCM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7RCM FirstGlance]. <br>
</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=7rcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rcm OCA], [https://pdbe.org/7rcm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rcm RCSB], [https://www.ebi.ac.uk/pdbsum/7rcm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rcm ProSAT]</span></td></tr>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ADP:ADENOSINE-5-DIPHOSPHATE'>ADP</scene>, <scene name='pdbligand=GLA:ALPHA+D-GALACTOSE'>GLA</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=NA:SODIUM+ION'>NA</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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=7rcm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7rcm OCA], [https://pdbe.org/7rcm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7rcm RCSB], [https://www.ebi.ac.uk/pdbsum/7rcm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7rcm ProSAT]</span></td></tr>
</table>
</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> 
== Function ==
[[https://www.uniprot.org/uniprot/GALK1_HUMAN GALK1_HUMAN]] Major enzyme for galactose metabolism.
<div style="background-color:#fffaf0;">
== 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 &lt; 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<ref>PMID:34491744</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7rcm" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
__TOC__
</StructureSection>
</StructureSection>
[[Category: Galactokinase]]
[[Category: Large Structures]]
[[Category: Large Structures]]
[[Category: Whitby FG]]
[[Category: Whitby, F G]]
[[Category: Adp]]
[[Category: Disulfide]]
[[Category: Galactose]]
[[Category: Galk]]
[[Category: Sugar binding protein]]

Revision as of 08:57, 6 October 2021

Crystal Structure of ADP-bound GalactokinaseCrystal Structure of ADP-bound Galactokinase

Structural highlights

7rcm is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:, , , , ,
Activity:Galactokinase, with EC number 2.7.1.6
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

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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
  4. ↑ 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
  5. ↑ Timson DJ, Reece RJ. Functional analysis of disease-causing mutations in human galactokinase. Eur J Biochem. 2003 Apr;270(8):1767-74. PMID:12694189
  6. ↑ 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
  7. ↑ 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

7rcm, resolution 2.10Å

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)Proteopedia Page Contributors and Editors (what is this?)

OCA
Retrieved from "https://proteopedia.openfox.io/wiki/index.php?title=7rcm&oldid=3456705"