PDBsum entry 1a42

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Lyase PDB id
Protein chain
256 a.a.
Waters ×55

References listed in PDB file
Key reference
Title Structures of murine carbonic anhydrase IV and human carbonic anhydrase ii complexed with brinzolamide: molecular basis of isozyme-Drug discrimination.
Authors T.Stams, Y.Chen, P.A.Boriack-Sjodin, J.D.Hurt, J.Liao, J.A.May, T.Dean, P.Laipis, D.N.Silverman, D.W.Christianson.
Ref. Protein Sci, 1998, 7, 556-563. [DOI no: 10.1002/pro.5560070303]
PubMed id 9541386
Carbonic anhydrase IV (CAIV) is a membrane-associated enzyme anchored to plasma membrane surfaces by a phosphatidylinositol glycan linkage. We have determined the 2.8-angstroms resolution crystal structure of a truncated, soluble form of recombinant murine CAIV. We have also determined the structure of its complex with a drug used for glaucoma therapy, the sulfonamide inhibitor brinzolamide (Azopt). The overall structure of murine CAIV is generally similar to that of human CAIV; however, some local structural differences are found in the active site resulting from amino acid sequence differences in the "130's segment" and the residue-63 loop (these may affect the nearby catalytic proton shuttle, His-64). Similar to human CAIV, the C-terminus of murine CAIV is surrounded by a substantial electropositive surface potential that may stabilize the interaction with the phospholipid membrane. Binding interactions observed for brinzolamide rationalize the generally weaker affinity of inhibitors used in glaucoma therapy toward CAIV compared with CAII.
Figure 6.
Fig. 6. Differenceelectrondensitymap of thehumanCAII-brinzolamide complex,generatedwithFouriercoefficients IF,I - I,] nd phasescal- culatedfromthefnalmodelminustheatoms of brinzolamide(contoured at 3~ ). Thesulfonamidenitrogen of brinzolamide coordinates tozncand displaces zinc-boundhydroxide,therebymaintainingtetrahedralmetalco- ordinationgeometry.Thealiphatictail of brinzolamidemakesvander Waals contactwihPhe-131and Pro-202.
Figure 8.
Fig. 8. CAII-brinzolamide and CAIV-brinzolamide complexes (upper left and lower right, respectively). Brinzolamide is magenta; the CAIV- membrane interaction is represented schematically, where the GPI anchor (yellow) attached to the C-terminus of the enzyme is inserted into the CAIV orientation by interacting with negatively charged phosphates (red). Figure prepared with MOLSCRIPT (Kraulis, 1991) and Raster 3D (Bacon & Anderson, 1988; Merritt & Murphy, 1994).
The above figures are reprinted from an Open Access publication published by the Protein Society: Protein Sci (1998, 7, 556-563) copyright 1998.
Secondary reference #1
Title Structural analysis of inhibitor binding to human carbonic anhydrase ii.
Authors P.A.Boriack-Sjodin, S.Zeitlin, H.H.Chen, L.Crenshaw, S.Gross, A.Dantanarayana, P.Delgado, J.A.May, T.Dean, D.W.Christianson.
Ref. Protein Sci, 1998, 7, 2483-2489. [DOI no: 10.1002/pro.5560071201]
PubMed id 9865942
Full text Abstract
Figure 3.
Fig. 3. Superposition of theatomiccoordinates of AL5300 (gree)and AL5415 (red).Forclarity, only theproteinatoms of CAII inthe CAII- AL5415complexareshown Primarysulfonamide-zinccoordi- nationgeometry,andedge-to-faceinteractionsbetweenthethophene ``tail'' of theinhibitorand Phel31, areidenticalinthetwo complees. Binding differenceare localized totheConformationofthesecondarysulfonamide group.
Figure 6.
Fig. 6. Superpositionoftheatomiccoordinatesofbrinzolamide(Azoptm; AL4862, Kd = 0.13 nM) anddorzolamide(Trusoptm, Ki 0.37 nM, Greer et l., 994; Smithet al., 1994). thetwonewest CAII inhibitorsappoved for the treatmentofglaucoma.Brinzolamideisred;dorzolaide is green. Forclarity,onlytheproteinatomsoCAII in the CAII-L4862 (brizola- mide)complex are shown(yellow).Notethatthesix-memberedthiazene ring of rizolamideadopts a half-chair,conformation,whereasthesix- membeedthienoringofdorzolamideadopts a half-chair2conformation.
The above figures are reproduced from the cited reference which is an Open Access publication published by the Protein Society
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