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5sz4

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Revision as of 14:19, 6 November 2017

Carbonic anhydrase IX-mimic in complex with 4-(phenyl)-benzenesulfonamide

Structural highlights

5sz4 is a 1 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	, ,
Related:	5sz0, 5sz1, 5sz2, 5sz3, 5sz5, 5sz6, 5sz7
Gene:	CA2 (HUMAN)
Activity:	Carbonate dehydratase, with EC number 4.2.1.1
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 anhydrases (CAs) are implicated in a wide range of diseases, including the upregulation of isoforms CA IX and XII in many aggressive cancers. However, effective inhibition of disease-implicated CAs should minimally affect the ubiquitously expressed isoforms including CA I and II to improve directed distribution of the inhibitors to the cancer-associated isoforms and reduce side effects. Four benzenesulfonamide-based inhibitors were synthesized using the "tail approach" and display nM affinities for several CA isoforms. The crystal structures of the inhibitors bound to a CA IX-mimic and CA II are presented. Further in-silico modeling was performed with the inhibitors docked into CA I and XII to identify residues that contribute to or hinder their binding interactions. These structural studies demonstrate that active site residues lining the hydrophobic pocket, especially positions 92 and 131, dictate the positional binding and affinity of inhibitors and the tail groups modulate CA isoform specificity. Geometry optimizations were performed on each ligand in the crystal structures and showed the energetic penalties of the inhibitors' conformations were negligible compared to the gain of active site interactions. These studies further our understanding of obtaining isoform specificity when designing small molecule CA inhibitors.

Structure activity relationships of benzenesulfonamide-based inhibitors towards carbonic anhydrase isoform specificity.,Bhatt A, Mahon BP, Cruzeiro VW, Cornelio B, Laronze-Cochard M, Ceruso M, Sapi J, Rance GA, Khlobystov AN, Fontana A, Roitberg A, Supuran CT, Mc Kenna R Chembiochem. 2016 Nov 18. doi: 10.1002/cbic.201600513. PMID:27860128^[8]

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

References

↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ 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
↑ Bhatt A, Mahon BP, Cruzeiro VW, Cornelio B, Laronze-Cochard M, Ceruso M, Sapi J, Rance GA, Khlobystov AN, Fontana A, Roitberg A, Supuran CT, Mc Kenna R. Structure activity relationships of benzenesulfonamide-based inhibitors towards carbonic anhydrase isoform specificity. Chembiochem. 2016 Nov 18. doi: 10.1002/cbic.201600513. PMID:27860128 doi:http://dx.doi.org/10.1002/cbic.201600513

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5sz4"

@@ Line 3: / Line 3: @@
 <StructureSection load='5sz4' size='340' side='right' caption='[[5sz4]], [[Resolution|resolution]] 1.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5sz4]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SZ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SZ4 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5sz4]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5SZ4 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5SZ4 FirstGlance]. <br>
 </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=72D:4-(PHENYL)-BENZENESULFONAMIDE'>72D</scene>, <scene name='pdbligand=DMS:DIMETHYL+SULFOXIDE'>DMS</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
 <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[5sz0|5sz0]], [[5sz1|5sz1]], [[5sz2|5sz2]], [[5sz3|5sz3]], [[5sz5|5sz5]], [[5sz6|5sz6]], [[5sz7|5sz7]]</td></tr>
+<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CA2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
 <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=4.2.1.1 4.2.1.1] </span></td></tr>
 <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5sz4 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5sz4 OCA], [http://pdbe.org/5sz4 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5sz4 RCSB], [http://www.ebi.ac.uk/pdbsum/5sz4 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5sz4 ProSAT]</span></td></tr>
@@ Line 27: / Line 28: @@
 </StructureSection>
 [[Category: Carbonate dehydratase]]
+[[Category: Human]]
 [[Category: Bhatt, A]]
 [[Category: Cornelio, B]]

5sz4

From Proteopedia

Revision as of 14:19, 6 November 2017

Carbonic anhydrase IX-mimic in complex with 4-(phenyl)-benzenesulfonamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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