5jn9

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure for the complex of human carbonic anhydrase IV and ethoxyzolamide

Structural highlights

5jn9 is a 4 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 2.1Å
Ligands:	, , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

CAH4_HUMAN Defects in CA4 are the cause of retinitis pigmentosa type 17 (RP17) [MIM:600852. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP17 inheritance is autosomal dominant. Note=Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype.^[1]

Function

CAH4_HUMAN Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.^[2]

Publication Abstract from PubMed

Membrane-associated carbonic anhydrase (CA) isoform IV participates in carbon metabolism and pH homeostasis and is implicated in the development of eye diseases such as retinitis pigmentosa and glaucoma. A series of substituted benzenesulfonamides were designed and their binding affinity to CA IV was determined by fluorescent thermal shift assay and isothermal titration calorimetry (ITC). Compound [(4-chloro-2-phenylsulfanyl-5-sulfamoyl-benzoyl)amino]propyl acetate (19) bound CA IV with the K d of 1.0 nM and exhibited significant selectivity over the remaining 11 human CA isoforms. The compound could be developed as a drug targeting CA IV. Various forms of recombinant CA IV were produced in Escherichia coli and mammalian cell cultures. Comparison of their temperature stability in various buffers and salt solutions demonstrated that CA IV is most stable at slightly alkaline conditions and at elevated sodium sulfate concentrations. High-resolution X-ray crystallographic structures of ortho-Cl and meta-thiazole-substituted benzene sulfonamide in complex with CA IV revealed the position of and interactions between the ligand and the protein. Sulfonamide inhibitor binding to CA IV is linked to several reactions-the deprotonation of the sulfonamide amino group, the protonation of CA-Zn(II)-bound hydroxide at the active site of CA IV, and the compensating reactions of the buffer. The dissection of binding-linked reactions yielded the intrinsic thermodynamic parameters, characterizing the interaction between CA IV and the sulfonamides in the binding-able protonation forms, including Gibbs energy, enthalpy, and entropy, that could be used for the characterization of binding to any CA in the process of drug design.

Intrinsic thermodynamics of high affinity inhibitor binding to recombinant human carbonic anhydrase IV.,Mickeviciute A, Timm DD, Gedgaudas M, Linkuviene V, Chen Z, Waheed A, Michailoviene V, Zubriene A, Smirnov A, Capkauskaite E, Baranauskiene L, Jachno J, Revuckiene J, Manakova E, Grazulis S, Matuliene J, Di Cera E, Sly WS, Matulis D Eur Biophys J. 2017 Oct 3. pii: 10.1007/s00249-017-1256-0. doi:, 10.1007/s00249-017-1256-0. PMID:28975383^[3]

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

References

↑ Yang Z, Alvarez BV, Chakarova C, Jiang L, Karan G, Frederick JM, Zhao Y, Sauve Y, Li X, Zrenner E, Wissinger B, Hollander AI, Katz B, Baehr W, Cremers FP, Casey JR, Bhattacharya SS, Zhang K. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet. 2005 Jan 15;14(2):255-65. Epub 2004 Nov 24. PMID:15563508 doi:ddi023
↑ Yang Z, Alvarez BV, Chakarova C, Jiang L, Karan G, Frederick JM, Zhao Y, Sauve Y, Li X, Zrenner E, Wissinger B, Hollander AI, Katz B, Baehr W, Cremers FP, Casey JR, Bhattacharya SS, Zhang K. Mutant carbonic anhydrase 4 impairs pH regulation and causes retinal photoreceptor degeneration. Hum Mol Genet. 2005 Jan 15;14(2):255-65. Epub 2004 Nov 24. PMID:15563508 doi:ddi023
↑ Mickeviciute A, Timm DD, Gedgaudas M, Linkuviene V, Chen Z, Waheed A, Michailoviene V, Zubriene A, Smirnov A, Capkauskaite E, Baranauskiene L, Jachno J, Revuckiene J, Manakova E, Grazulis S, Matuliene J, Di Cera E, Sly WS, Matulis D. Intrinsic thermodynamics of high affinity inhibitor binding to recombinant human carbonic anhydrase IV. Eur Biophys J. 2017 Oct 3. pii: 10.1007/s00249-017-1256-0. doi:, 10.1007/s00249-017-1256-0. PMID:28975383 doi:http://dx.doi.org/10.1007/s00249-017-1256-0

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

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/5jn9"

@@ Line 3: / Line 3: @@
 <StructureSection load='5jn9' size='340' side='right'caption='[[5jn9]], [[Resolution|resolution]] 2.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[5jn9]] is a 4 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5JN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JN9 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[5jn9]] is a 4 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=5JN9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5JN9 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EZL:6-ETHOXY-1,3-BENZOTHIAZOLE-2-SULFONAMIDE'>EZL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
+</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.1&#8491;</td></tr>
-<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[5jn8|5jn8]], [[5jna|5jna]], [[5jnc|5jnc]], [[5jnd|5jnd]]</div></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=EZL:6-ETHOXY-1,3-BENZOTHIAZOLE-2-SULFONAMIDE'>EZL</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CA4 ([https://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'>[https://en.wikipedia.org/wiki/Carbonate_dehydratase Carbonate dehydratase], with EC number [https://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'>[https://proteopedia.org/fgij/fg.htm?mol=5jn9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5jn9 OCA], [https://pdbe.org/5jn9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5jn9 RCSB], [https://www.ebi.ac.uk/pdbsum/5jn9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5jn9 ProSAT]</span></td></tr>
 </table>
 == Disease ==
-[[https://www.uniprot.org/uniprot/CAH4_HUMAN CAH4_HUMAN]] Defects in CA4 are the cause of retinitis pigmentosa type 17 (RP17) [MIM:[https://omim.org/entry/600852 600852]]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP17 inheritance is autosomal dominant. Note=Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype.<ref>PMID:15563508</ref>
+[https://www.uniprot.org/uniprot/CAH4_HUMAN CAH4_HUMAN] Defects in CA4 are the cause of retinitis pigmentosa type 17 (RP17) [MIM:[https://omim.org/entry/600852 600852]. RP leads to degeneration of retinal photoreceptor cells. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well. RP17 inheritance is autosomal dominant. Note=Defective acid overload removal from retina and retinal epithelium, due to mutant CA4, is responsible for photoreceptor degeneration, indicating that impaired pH homeostasis is the most likely cause underlying the RP17 phenotype.<ref>PMID:15563508</ref>
 == Function ==
-[[https://www.uniprot.org/uniprot/CAH4_HUMAN CAH4_HUMAN]] Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.<ref>PMID:15563508</ref>
+[https://www.uniprot.org/uniprot/CAH4_HUMAN CAH4_HUMAN] Reversible hydration of carbon dioxide. May stimulate the sodium/bicarbonate transporter activity of SLC4A4 that acts in pH homeostasis. It is essential for acid overload removal from the retina and retina epithelium, and acid release in the choriocapillaris in the choroid.<ref>PMID:15563508</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 30: / Line 28: @@
 __TOC__
 </StructureSection>
-[[Category: Carbonate dehydratase]]
+[[Category: Homo sapiens]]
-[[Category: Human]]
 [[Category: Large Structures]]
-[[Category: Cera, E Di]]
+[[Category: Chen Z]]
-[[Category: Chen, Z]]
+[[Category: Di Cera E]]
-[[Category: Sly, W S]]
+[[Category: Sly WS]]
-[[Category: Waheed, A]]
+[[Category: Waheed A]]
-[[Category: Carbonic anhydrase]]
-[[Category: Inhibitor binding]]
-[[Category: Lyase]]
-[[Category: Lyase-lyase inhibitor complex]]

5jn9

From Proteopedia

Current revision

Crystal structure for the complex of human carbonic anhydrase IV and ethoxyzolamide

Structural highlights

Disease

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

Views

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