5ipz
From Proteopedia
Crystal structure of human carbonic anhydrase isozyme IV with 5-(2-amino-1,3-thiazol-4-yl)-2-chlorobenzenesulfonamide
Structural highlights
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 PubMedMembrane-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
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