9tye: Difference between revisions
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Created page with "'''Unreleased structure''' The entry 9tye is ON HOLD Authors: Alterio, V., De Simone, G. Description: Crystal structure of a phosphocoumarin derivative in complex with human carbonic anhydrase II Category: Unreleased Structures Category: De Simone, G Category: Alterio, V" |
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The | ==Crystal structure of a phosphocoumarin derivative in complex with human carbonic anhydrase II== | ||
<StructureSection load='9tye' size='340' side='right'caption='[[9tye]], [[Resolution|resolution]] 1.65Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[9tye]] 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=9TYE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9TYE 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]] 1.65Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=A1JX9:7-methoxy-2-oxidanyl-1,2$l^{5}-benzoxaphosphinine+2-oxide'>A1JX9</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=9tye FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9tye OCA], [https://pdbe.org/9tye PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9tye RCSB], [https://www.ebi.ac.uk/pdbsum/9tye PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9tye 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 == | |||
Phosphocoumarins and a first-in-class unsubstituted phosphoquinolinone are disclosed as previously unrecognized carbonic anhydrase (CA) inhibitors, displaying multimodal inhibition within a tunable coumarin-like scaffold. Acidic phosphocoumarins display inhibition of physiologically relevant human CAs, particularly tumor-associated isoforms IX and XII (K(I)s: 0.08-0.28 muM) through a composite, two-step mechanism: the ligand first anchors the zinc-bound water molecule before displacing it to directly coordinate the catalytic zinc ion, without CA-mediated hydrolysis. Conversely, a methyl-ester phosphocoumarin functions as an isoform-selective prodrug, undergoing CA-mediated cyclic phosphoester hydrolysis to selectively generate a potent hCA IX/XII inhibitor (K(I)s: 54-62 nM), whereas the phosphoquinolinone acts as a direct binder (K(I)s: 0.18-0.29 muM vs hCA IX/XII). The complementary mechanisms are supported by QM/MM and long-time scale MD simulations, crystallographic studies, (31)P NMR, HRMS, and MS/MS. Selected derivatives exhibit low-micromolar antiproliferative activity and induce apoptosis in cancer cells, fostering phosphorus-heterocycles as a mechanistically rich platform for isoform-selective CA inhibition and targeted drug design. | |||
Discovery of a Mixed and Prodrug-Like Inhibition Mechanism for Phosphocoumarins and Phosphoquinolinones against Human Carbonic Anhydrases.,Nocentini A, Giovannuzzi S, Alterio V, Bonardi A, Barons R, Zalubovskis R, Eldehna WM, Aronne R, Esposito D, Luchinat E, De Simone G, Bartolucci G, Gratteri P, Mori M, Supuran CT J Med Chem. 2026 Apr 29. doi: 10.1021/acs.jmedchem.6c00915. PMID:42055938<ref>PMID:42055938</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 9tye" style="background-color:#fffaf0;"></div> | ||
[[Category: Alterio | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | |||
[[Category: Large Structures]] | |||
[[Category: Alterio V]] | |||
[[Category: De Simone G]] | |||
