6yo2: Difference between revisions
No edit summary |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Meta-Carborane propyl-sulfonamide in complex with CA IX mimic== | ||
<StructureSection load='6yo2' size='340' side='right'caption='[[6yo2]], [[Resolution|resolution]] 1.20Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6yo2]] 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=6YO2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6YO2 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]] 1.2Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P6Q:Meta-Carborane+propyl-sulfonamide'>P6Q</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=6yo2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6yo2 OCA], [https://pdbe.org/6yo2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6yo2 RCSB], [https://www.ebi.ac.uk/pdbsum/6yo2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6yo2 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), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba- closo -dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba- closo -dodecaboranes with a different geometric position of carbon atoms. The closo - compounds from the ortho - and meta - series were then degraded to corresponding 11-vertex dicarba- nido -undecaborate(1-) anions. All the compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant ( K i) and selectivity towards CA IX. Decreasing trends in K i and selectivity index (S I ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity. | |||
Direct Introduction of an Alkylsulfonamido Group on C-sites of Isomeric Carboranes; the Influence of Stereochemistry on Inhibitory Activity Against Cancer-associated Carbonic Anhydrase IX Isoenzyme.,Nekvinda J, Kugler M, Holub J, El Anwar S, Brynda J, Pospisilova K, Ruzickova Z, Rezacova P, Gruner B Chemistry. 2020 Aug 5. doi: 10.1002/chem.202002809. PMID:32757220<ref>PMID:32757220</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 6yo2" 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: Brynda J]] | |||
[[Category: Kugler M]] | |||
[[Category: Pospisilova K]] | |||
[[Category: Rezacova P]] | |||
Latest revision as of 16:31, 24 January 2024
Meta-Carborane propyl-sulfonamide in complex with CA IX mimicMeta-Carborane propyl-sulfonamide in complex with CA IX mimic
Structural highlights
DiseaseCAH2_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] FunctionCAH2_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 PubMedCarbonic Anhydrase IX (CA IX), a tumor-associated metalloenzyme, represents a validated target for cancer therapy and diagnostics. Herein, we report the inhibition properties of isomeric families of sulfonamidopropyl-dicarba- closo -dodecaboranes group(s) prepared using a new direct five-step synthesis from the corresponding parent cages. The protocol offers a reliable solution for synthesis of singly and doubly substituted dicarba- closo -dodecaboranes with a different geometric position of carbon atoms. The closo - compounds from the ortho - and meta - series were then degraded to corresponding 11-vertex dicarba- nido -undecaborate(1-) anions. All the compounds show in vitro enzymatic activity against CA IX in the low nanomolar or subnanomolar range. This is accompanied by clear isomer dependence of the inhibition constant ( K i) and selectivity towards CA IX. Decreasing trends in K i and selectivity index (S I ) values are observed with increasing separation of the cage carbon atoms. Interactions of compounds with the active sites of CA IX were explored with X-ray crystallography, and eight high-resolution crystal structures uncovered the structural basis of inhibition potency and selectivity. Direct Introduction of an Alkylsulfonamido Group on C-sites of Isomeric Carboranes; the Influence of Stereochemistry on Inhibitory Activity Against Cancer-associated Carbonic Anhydrase IX Isoenzyme.,Nekvinda J, Kugler M, Holub J, El Anwar S, Brynda J, Pospisilova K, Ruzickova Z, Rezacova P, Gruner B Chemistry. 2020 Aug 5. doi: 10.1002/chem.202002809. PMID:32757220[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||