PDBsum entry 1bcd

Lyase(oxo-acid)

PDB id: 1bcd

Contents

Protein chain

258 a.a.

Ligands

FMS

Metals

_ZN

Waters ×215

References listed in PDB file

Key reference

Title

The structure of a complex between carbonic anhydrase ii and a new inhibitor, Trifluoromethane sulphonamide.

Authors

K.Håkansson, A.Liljas.

Ref.

Febs Lett, 1994, 350, 319-322. [DOI no: 10.1016/0014-5793(94)00798-5]

PubMed id

8070585

Abstract

It has recently been shown that aliphatic sulphonamides are good inhibitors of carbonic anhydrase (CA) provided that the pK of the sulphonamide is low. We have determined the structure of the complex between CAII and CF3SO2NH2 by X-ray crystallographic methods. The nitrogen of the sulphonamide is bound to the zinc ion of the enzyme in the usual manner. The other parts of the inhibitor show a different mode of binding from aromatic sulphonamides since the trifluoromethyl group is bound at the hydrophobic part of the active site instead of pointing out from the active site. It should be possible to design new inhibitors specific for the different isoenzymes, starting from the present structure.

Figure 1.
Fig. 1. (A) The active site of carbonic anhydrase complexed the inhibitor CF3SO2NH-. Difference electron maps were calculated after refinement of native coordinates without waters 263,292, 318,338 and 389. Positive (continous lines) and negative (broken lines) [Fo [ - [ Fc[ contours were drawn at +3 or. (B) The inhibitor from (A) with all atoms labelled.

Figure 2.
Fig. 2. The molecular structure of carbonic anhydrase complexed with is compared with the complex with acetazolamide (broken The polypeptide chain f the acetazolamide complex [251 is not since the conformatons are virtually the same in the two cases.

The above figures are reprinted by permission from the Federation of European Biochemical Societies: Febs Lett (1994, 350, 319-322) copyright 1994.

Secondary reference #1

Title

Refined structure of the aminobenzolamide complex of human carbonic anhydrase ii at 1.9 a and sulphonamide modelling of bovine carbonic anhydrase III.

Authors

J.Vidgren, A.Svensson, A.Liljas.

Ref.

Int J Biol Macromol, 1993, 15, 97.

PubMed id

8485108

Secondary reference #2

Title

Structure of native and apo carbonic anhydrase ii and structure of some of its anion-Ligand complexes.

Authors

K.Håkansson, M.Carlsson, L.A.Svensson, A.Liljas.

Ref.

J Mol Biol, 1992, 227, 1192-1204. [DOI no: 10.1016/0022-2836(92)90531-N]

PubMed id

1433293

Figure 1.
Figure 1. The molecules involved in he hydrogen bond chain between His64 an the zinc water molecule in native carbnic anhydrase at pH 7%. Distances and angles are; 64Nd' -2920HH-3180HH: (322 A. 196.7''. 2.73 A) and 2920HH-3180HH-2630HH: (2.7 A, lOS.l'', 2.79 A).

Figure 3.
Figure 3. A larger view than in Fig. 2 of the active site. Note the ydrophobic nature of the right hand sde of the cleft ith valins 121, 143 and 207, leucines 141 and 198 and tryptophan 209.

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #3

Title

Structure of cobalt carbonic anhydrase complexed with bicarbonate.

Authors

K.Håkansson, A.Wehnert.

Ref.

J Mol Biol, 1992, 228, 1212-1218. [DOI no: 10.1016/0022-2836(92)90327-G]

PubMed id

1474587

Figure 1.
Figure 1. The Co(II)carbonic anhydrasebicarbnate complex. Difference electron maps were calculated after refinement of native co-ordinates without waters molecules 263 and 338 and with Co(H) instead of Zn(II). Positive (continuous lines) and negative (broken lines) IF,/ IF,1 contours were rawn at +3a. The broken thinner molecular drawings renresent the bindinn sites for formate in native CA11 (Hbkansson et a.Z., 1992) and for bicarbonate in mant T200HUCAIi (Xue t al., 1992y.

Figure 2.
Figure 2. The carbonic anhydrase mechanism of Hakansson et ai. (1992) in stereo. The `-states'' refer to Fig. 8 in that paper. (a) (State 1) Native carbonic anhydrase II: with a zinc hydroxyl (23) at the 4th (tetrahedral) co-ordination site. b) (State 2,3) A carbon dioxide molecule (500) is bound to the enzyme and is electrophilically activated. This is the crystal structure of carbonic anhydrase complexed with cyanate (Lindahl et aZ., 19923). The broken lines represent the binding of the sulfonamide group in the carbonic anhydrseDiamo complex; which may be analogous to an early tage of nucleophilic attack on the carbon dioxide. (c) (State 4) This state s hypotheticl. The zinc hydroxyl is now a part of the bicarbonate product and is bound at the zin water position wit,h the tetrahedral geometry o t,he native enzyme. The oxygen atom itself is also tetrahedrally surrounded by water molecule 318, Thr1990Y, the zinc ion and the bicarbonate arbon atom. The position of bicaronate is similar to what is found in th mutant T200H-bicarbonate complex, although the solvent structures are different in the 2 cases (Xue et al.; 1992) (d) (State 5) Water molecule 318 is leaving its normal position and makes a long co-ordination contact with te zinc ion and is now called 263. The bicarbonate group is pushed away to a longer co-ordination distance. This is the crysta structure rported in this paper. The bicarbonate molecule is now free to leave. The zinc water then takes its tetrahedral postin and a solution molecule takes the vacant 318 osition. This step is co-ordinated with the proton shuttle (Liang & Lipscomb, 1989), where 1 of the zinc water protons is shuttled through water molecules 31%292.Hi64 and released to a nearby buffer molecule in order to omplete the cycle and regenerate the zinc hydroxide.

The above figures are reproduced from the cited reference with permission from Elsevier

Secondary reference #4

Title

Refined structure of the acetazolamide complex of human carbonic anhydrase ii at 1.9 a.

Authors

J.Vidgren, A.Liljas, N.P.Walker.

Ref.

Int J Biol Macromol, 1990, 12, 342-344.

PubMed id

2128470