4riu: Difference between revisions

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New page: '''Unreleased structure''' The entry 4riu is ON HOLD Authors: Mahon, B.P., McKenna, R. Description: A Carbonic Anhydrase IX Mimic in Complex with a Saccharin-Based Inhibitor
 
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'''Unreleased structure'''


The entry 4riu is ON HOLD
==A Carbonic Anhydrase IX Mimic in Complex with a Saccharin-Based Inhibitor==
<StructureSection load='4riu' size='340' side='right'caption='[[4riu]], [[Resolution|resolution]] 1.65&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[4riu]] 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=4RIU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4RIU FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.651&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=3QR:[1-(1,1-DIOXIDO-3-OXO-2,3-DIHYDRO-1,2-BENZOTHIAZOL-6-YL)-1H-1,2,3-TRIAZOL-4-YL]METHYL+ALPHA-L-IDOPYRANOSIDE'>3QR</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=4riu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4riu OCA], [https://pdbe.org/4riu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4riu RCSB], [https://www.ebi.ac.uk/pdbsum/4riu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4riu ProSAT]</span></td></tr>
</table>
== Disease ==
[https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:[https://omim.org/entry/259730 259730]; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.<ref>PMID:1928091</ref> <ref>PMID:1542674</ref> <ref>PMID:8834238</ref> <ref>PMID:9143915</ref> <ref>PMID:15300855</ref>
== Function ==
[https://www.uniprot.org/uniprot/CAH2_HUMAN CAH2_HUMAN] Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.<ref>PMID:10550681</ref> <ref>PMID:11831900</ref>
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (&gt;50-fold for SAC and &gt;1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.


Authors: Mahon, B.P., McKenna, R.
Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.,Mahon BP, Hendon AM, Driscoll JM, Rankin GM, Poulsen SA, Supuran CT, McKenna R Bioorg Med Chem. 2015 Feb 15;23(4):849-54. doi: 10.1016/j.bmc.2014.12.030. Epub, 2014 Dec 23. PMID:25614109<ref>PMID:25614109</ref>


Description: A Carbonic Anhydrase IX Mimic in Complex with a Saccharin-Based Inhibitor
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 4riu" style="background-color:#fffaf0;"></div>
 
==See Also==
*[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Mahon BP]]
[[Category: McKenna R]]

Latest revision as of 20:50, 20 September 2023

A Carbonic Anhydrase IX Mimic in Complex with a Saccharin-Based InhibitorA Carbonic Anhydrase IX Mimic in Complex with a Saccharin-Based Inhibitor

Structural highlights

4riu 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 1.651Å
Ligands:, ,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CAH2_HUMAN Defects in CA2 are the cause of osteopetrosis autosomal recessive type 3 (OPTB3) [MIM:259730; also known as osteopetrosis with renal tubular acidosis, carbonic anhydrase II deficiency syndrome, Guibaud-Vainsel syndrome or marble brain disease. Osteopetrosis is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. The disorder occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Autosomal recessive osteopetrosis is usually associated with normal or elevated amount of non-functional osteoclasts. OPTB3 is associated with renal tubular acidosis, cerebral calcification (marble brain disease) and in some cases with mental retardation.[1] [2] [3] [4] [5]

Function

CAH2_HUMAN Essential for bone resorption and osteoclast differentiation (By similarity). Reversible hydration of carbon dioxide. Can hydrate cyanamide to urea. Involved in the regulation of fluid secretion into the anterior chamber of the eye.[6] [7]

Publication Abstract from PubMed

Carbonic anhydrase IX (CA IX) is a key modulator of aggressive tumor behavior and a prognostic marker and target for several cancers. Saccharin (SAC) based compounds may provide an avenue to overcome CA isoform specificity, as they display both nanomolar affinity and preferential binding, for CA IX compared to CA II (>50-fold for SAC and >1000-fold when SAC is conjugated to a carbohydrate moiety). The X-ray crystal structures of SAC and a SAC-carbohydrate conjugate bound to a CA IX-mimic are presented and compared to CA II. The structures provide substantial new insight into the mechanism of SAC selective CA isoform inhibition.

Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors.,Mahon BP, Hendon AM, Driscoll JM, Rankin GM, Poulsen SA, Supuran CT, McKenna R Bioorg Med Chem. 2015 Feb 15;23(4):849-54. doi: 10.1016/j.bmc.2014.12.030. Epub, 2014 Dec 23. PMID:25614109[8]

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

See Also

References

  1. ↑ Venta PJ, Welty RJ, Johnson TM, Sly WS, Tashian RE. Carbonic anhydrase II deficiency syndrome in a Belgian family is caused by a point mutation at an invariant histidine residue (107 His----Tyr): complete structure of the normal human CA II gene. Am J Hum Genet. 1991 Nov;49(5):1082-90. PMID:1928091
  2. ↑ Roth DE, Venta PJ, Tashian RE, Sly WS. Molecular basis of human carbonic anhydrase II deficiency. Proc Natl Acad Sci U S A. 1992 Mar 1;89(5):1804-8. PMID:1542674
  3. ↑ Soda H, Yukizane S, Yoshida I, Koga Y, Aramaki S, Kato H. A point mutation in exon 3 (His 107-->Tyr) in two unrelated Japanese patients with carbonic anhydrase II deficiency with central nervous system involvement. Hum Genet. 1996 Apr;97(4):435-7. PMID:8834238
  4. ↑ Hu PY, Lim EJ, Ciccolella J, Strisciuglio P, Sly WS. Seven novel mutations in carbonic anhydrase II deficiency syndrome identified by SSCP and direct sequencing analysis. Hum Mutat. 1997;9(5):383-7. PMID:9143915 doi:<383::AID-HUMU1>3.0.CO;2-5 10.1002/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5
  5. ↑ Shah GN, Bonapace G, Hu PY, Strisciuglio P, Sly WS. Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. Hum Mutat. 2004 Sep;24(3):272. PMID:15300855 doi:10.1002/humu.9266
  6. ↑ Briganti F, Mangani S, Scozzafava A, Vernaglione G, Supuran CT. Carbonic anhydrase catalyzes cyanamide hydration to urea: is it mimicking the physiological reaction? J Biol Inorg Chem. 1999 Oct;4(5):528-36. PMID:10550681
  7. ↑ Kim CY, Whittington DA, Chang JS, Liao J, May JA, Christianson DW. Structural aspects of isozyme selectivity in the binding of inhibitors to carbonic anhydrases II and IV. J Med Chem. 2002 Feb 14;45(4):888-93. PMID:11831900
  8. ↑ Mahon BP, Hendon AM, Driscoll JM, Rankin GM, Poulsen SA, Supuran CT, McKenna R. Saccharin: A lead compound for structure-based drug design of carbonic anhydrase IX inhibitors. Bioorg Med Chem. 2015 Feb 15;23(4):849-54. doi: 10.1016/j.bmc.2014.12.030. Epub, 2014 Dec 23. PMID:25614109 doi:http://dx.doi.org/10.1016/j.bmc.2014.12.030

4riu, resolution 1.65Å

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