A.E Eriksson

Bio: A.E Eriksson is an academic researcher from Uppsala University. The author has contributed to research in topics: Active site & Hydrogen bond. The author has an hindex of 3, co-authored 3 publications receiving 762 citations.

Refined structure of human carbonic anhydrase II at 2.0 A resolution.

Abstract: The structure of human erythrocytic carbonic anhydrase II has been refined by constrained and restrained structure–factor least-squares refinement at 2.0 A resolution. The conventional crystallographic R value is 17.3%. Of 167 solvent molecules associated with the protein, four are buried and stabilize secondary structure elements. The zinc ion is ligated to three histidyl residues and one water molecule in a nearly tetrahedral geometry. In addition to the zinc-bound water, seven more water molecules are identified in the active site. Assuming that Glu-106 is deprotonated at pH 8.5, some of the hydrogen bond donor–acceptor relations in the active site can be assigned and are described here in detail. The Oγ1 atom of Thr-199 donates its proton to the Oe1 atom of Glu-106 and can function as a hydrogen bond acceptor only in additional hydrogen bonds.

Crystallographic studies of inhibitor binding sites in human carbonic anhydrase II: a pentacoordinated binding of the SCN- ion to the zinc at high pH.

Abstract: The binding of four inhibitors--mercuric ion, 3-acetoxymercuri-4-aminobenzenesulfonamide (AMS), acetazolamide (Diamox), and thiocyanate ion--to human carbonic anhydrase II (HCA II) has been studied with X-ray crystallography The binding of mercury to HCA II at pH 70 has been investigated at 31 A resolution Mercuric ions are observed at both nitrogens in the His-64 ring One of these sites is pointing toward the zinc ion The only other binding site for mercury is at Cys-206 The binding of the two sulfonamide inhibitors AMS and Diamox, has been reinvestigated at 20 and 30 A, respectively Only the nitrogen of the sulfonamide group binds to the zinc ion replacing the hydroxyl ion The sulfonamide oxygen closest to the zinc ion is 31 A away Thus the tetrahedral geometry of the zinc is retained, refuting earlier models of a pentacoordinated zinc The structure of the thiocyanate complex has been investigated at pH 85 and the structure has been refined at 19 A resolution using the least-squares refinement program PROLSQ The crystallographic R factor is 176% The zinc ion is pentacoordinated with the anion as well as a water molecule bound in addition to the three histidine residues The nitrogen atom of the SCN- ion is 19 A from the zinc ion but shifted 13 A with respect to the hydroxyl ion in the native structure and at van der Waals' distance from the O gamma l atom of Thr-199 This is due to the inability of the O gamma l atom of Thr-199 to serve as a hydrogen bond donor, thus repelling the nonprotonated nitrogen The SCN- molecule reaches into the deep end of the active site cavity where the sulfur atom has displaced the so-called "deep" water molecule of the native enzyme The zinc-bound water molecule is 22 A from the zinc ion and 24 A from the SCN- nitrogen In addition, this water is hydrogen bonded to the O gamma l atom of Thr-199 and to another water molecule We have observed that solvent and inhibitor molecules have three possible binding sites on the zinc ion and their significance for the catalysis and inhibition of HCA II will be discussed All available crystallographic data are consistent with a proposed catalytic mechanism in which both the OH moiety and one oxygen of the substrate HCO3- ion are ligated to the zinc ion

Refined structure of bovine carbonic anhydrase III at 2.0 Å resolution

Abstract: The three-dimensional structure of bovine carbonic anhydrase III (BCA III) from red skeletal muscle cells has been determined by molecular replacement methods. The structure has been refined at 2.0 A resolution by both constrained and restrained structure-factor least squares refinement. The current crystallographic R-value is 19.2% and 121 solvent molecules have so far been found associated with the protein. The structure is highly similar to the refined structure of human carbonic anhydrase II. Some differences in amino acid sequence and structure between the two isoenzymes are discussed. In BCA III, Lys 64 and Arg 91 (His 64 and Ile 91 in HCA II) are both pointing out from the active site cavity forming salt bridges with Glu 4 and Asp 72 (His 4 and Asp 72 in HCA II), respectively. However, Arg 67 and Phe 198 (Asn 67 and Leu 198 in HCA II) are oriented towards the zinc ion and significantly reduce the volume of the active site cavity. Phe 198 particularly reduces the size of the substrate binding region at the "deep water" position at the bottom of the cavity and we suggest that this is one of the major reasons for the differences in catalytic properties of isoenzyme III as compared to isozyme II.

Structural and Functional Aspects of Metal Sites in Biology

Abstract: For present purposes, a protein-bound metal site consists of one or more metal ions and all protein side chain and exogenous bridging and terminal ligands that define the first coordination sphere of each metal ion. Such sites can be classified into five basic types with the indicated functions: (1) structural -- configuration (in part) of protein tertiary and/or quaternary structure; (2) storage -- uptake, binding, and release of metals in soluble form: (3) electron transfer -- uptake, release, and storage of electrons; (4) dioxygen binding -- metal-O{sub 2} coordination and decoordination; and (5) catalytic -- substrate binding, activation, and turnover. The authors present here a classification and structure/function analysis of native metal sites based on these functions, where 5 is an extensive class subdivided by the type of reaction catalyzed. Within this purview, coverage of the various site types is extensive, but not exhaustive. The purpose of this exposition is to present examples of all types of sites and to relate, insofar as is currently feasible, the structure and function of selected types. The authors largely confine their considerations to the sites themselves, with due recognition that these site features are coupled to protein structure at all levels. In themore » next section, the coordination chemistry of metalloprotein sites and the unique properties of a protein as a ligand are briefly summarized. Structure/function relationships are systematically explored and tabulations of structurally defined sites presented. Finally, future directions in bioinorganic research in the context of metal site chemistry are considered. 620 refs.« less

Carbonic anhydrase inhibitors

Abstract: A carbonic anhydrase IX (CA IX) inhibitor which comprises a compound of general formula: R-NH-CX-NH-(CH 2 ) n -Ar-Q-SO 2 -NH 2 or a pharmaceutically-acceptable salt, derivative or prodrug thereof; wherein n = 0, 1 or 2; Q is O or NH; X is O or S; and R comprises an organic substituent group.

Function and mechanism of zinc metalloenzymes.

Abstract: Zinc is required for the activity of > 300 enzymes, covering all six classes of enzymes. Zinc binding sites in proteins are often distorted tetrahedral or trigonal bipyramidal geometry, made up of the sulfur of cysteine, the nitrogen of histidine or the oxygen of aspartate and glutamate, or a combination. Zinc in proteins can either participate directly in chemical catalysis or be important for maintaining protein structure and stability. In all catalytic sites, the zinc ion functions as a Lewis acid. Researchers in our laboratory are dissecting the determinants of molecular recognition and catalysis in the zinc-binding site of carbonic anhydrase. These studies demonstrate that the chemical nature of the direct ligands and the structure of the surrounding hydrogen bond network are crucial for both the activity of carbonic anhydrase and the metal ion affinity of the zinc-binding site. An understanding of naturally occurring zinc-binding sites will aid in creating de novo zinc-binding proteins and in designing new metal sites in existing proteins for novel purposes such as to serve as metal ion biosensors.