|
|
| (18 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:1cnw.jpg|left|200px]]<br /><applet load="1cnw" size="350" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1cnw, resolution 2.0Å" /> | |
| - | '''SECONDARY INTERACTIONS SIGNIFICANTLY REMOVED FROM THE SULFONAMIDE BINDING POCKET OF CARBONIC ANHYDRASE II INFLUENCE BINDING CONSTANTS'''<br /> | |
| | | | |
| - | ==Overview== | + | ==SECONDARY INTERACTIONS SIGNIFICANTLY REMOVED FROM THE SULFONAMIDE BINDING POCKET OF CARBONIC ANHYDRASE II INFLUENCE BINDING CONSTANTS== |
| - | A series of competitive inhibitors of carbonic anhydrase II (CAII; EC 4.2.1.1) that consists of oligo(ethylene glycol) units attached to p-benzenesulfonamides with pendant amino acids, H2NSO2C6H4CONHCH2CH2OCH2CH2OCH2CH2NHCOCHRNH3+, have been synthesized and examined using competitive fluorescence assays. Three of the strongest inhibitors, designated EG3NH3+, EG3GlyNH3+, and EG3PheNH3+, have been studied by X-ray crystallographic methods at limiting resolutions of 1.9, 2.0, and 2.3 A, respectively. The sulfonamide-zinc binding modes and the association of the ethylene glycol linkers to the hydrophobic patch of the active site are similar in all three inhibitors. Differences in the values of Kd are therefore not due to differences in zinc coordination or to differences in the modes of enzyme-glycol association but instead appear to arise from interaction of the pendant amino acids with the surface of the protein. These pendant groups are, however, not sufficiently ordered to be visible in electron density maps. Thus, structural variations of inhibitors at locations distant from the primary binding (i.e., the sulfonamide group) site affect the overall binding affinities of inhibitors (e.g., Kd (EG3PheNH3+) = 14 nM as compared with Kd (EG3GluNH3+) = 100 nM).
| + | <StructureSection load='1cnw' size='340' side='right'caption='[[1cnw]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1cnw]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. The January 2004 RCSB PDB [https://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/index.html Molecule of the Month] feature on ''Carbonic Anhydrase'' by Shuchismita Dutta and David S. Goodsell is [https://dx.doi.org/10.2210/rcsb_pdb/mom_2004_1 10.2210/rcsb_pdb/mom_2004_1]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CNW OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1CNW 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]] 2Å</td></tr> |
| | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EG1:AMINOMETHYLENECARBONYLAMINODI(ETHYLOXY)ETHYLAMINOCARBONYLBENZENESULFONAMIDE'>EG1</scene>, <scene name='pdbligand=HG:MERCURY+(II)+ION'>HG</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=1cnw FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1cnw OCA], [https://pdbe.org/1cnw PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1cnw RCSB], [https://www.ebi.ac.uk/pdbsum/1cnw PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1cnw 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> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/cn/1cnw_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1cnw ConSurf]. |
| | + | <div style="clear:both"></div> |
| | | | |
| - | ==Disease== | + | ==See Also== |
| - | Known disease associated with this structure: Osteopetrosis, autosomal recessive 3, with renal tubular acidosis OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=611492 611492]]
| + | *[[Carbonic anhydrase 3D structures|Carbonic anhydrase 3D structures]] |
| - | | + | == References == |
| - | ==About this Structure== | + | <references/> |
| - | 1CNW is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with <scene name='pdbligand=ZN:'>ZN</scene>, <scene name='pdbligand=HG:'>HG</scene> and <scene name='pdbligand=EG1:'>EG1</scene> as [http://en.wikipedia.org/wiki/ligands ligands]. The following page contains interesting information on the relation of 1CNW with [[http://pdb.rcsb.org/pdb/static.do?p=education_discussion/molecule_of_the_month/pdb49_1.html Carbonic Anhydrase]]. Active as [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] Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1CNW OCA].
| + | __TOC__ |
| - | | + | </StructureSection> |
| - | ==Reference==
| + | |
| - | Secondary interactions significantly removed from the sulfonamide binding pocket of carbonic anhydrase II influence inhibitor binding constants., Boriack PA, Christianson DW, Kingery-Wood J, Whitesides GM, J Med Chem. 1995 Jun 23;38(13):2286-91. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=7608893 7608893]
| + | |
| - | [[Category: Carbonate dehydratase]]
| + | |
| | [[Category: Carbonic Anhydrase]] | | [[Category: Carbonic Anhydrase]] |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Boriack, P A.]] | + | [[Category: RCSB PDB Molecule of the Month]] |
| - | [[Category: Christianson, D W.]] | + | [[Category: Boriack PA]] |
| - | [[Category: EG1]] | + | [[Category: Christianson DW]] |
| - | [[Category: HG]]
| + | |
| - | [[Category: ZN]]
| + | |
| - | [[Category: lyase (oxo-acid)]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 12:08:02 2008''
| + | |
| Structural highlights
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]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
See Also
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
|
