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  • 1
    ISSN: 0887-3585
    Keywords: thrombin ; bifunctional inhibitor ; crystal structure ; hirutonis ; drugdesing ; Chemistry ; Biochemistry and Biotechnology
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: The crystal structure of the complexes of hirutonin-2 and hirutonin-6 with human α-thrombin have been solved and refined to R-factors of 0.169 (2.0 Å resolution) and 0.162 (201Å), respectively. Hirutonins belong to a family of bifunctional inhibitors bearing a noncleavable moiety mimicking the scissile bond. Hirutonin-2 is an analog of (D)Phe-Pro-Arg-Gly-hirudin49-65; hirutonin-6 has the same N-terminal tripeptide connected to a shortened fibrinogen exosite-binding part by a short, non-peptidyl linker. The hirutonin-6 molecule is well defined in the electron density with the exception of the C-terminal Leu-h61. The linker follows near the bottom of the canyon connecting the active site with the exosite, forms a short antiparallel β-sheet-like arrangement with Leu-40-Leu41 and makes van der Waals contacts with Glu39-Leu40-Leu41 of thrombin. In the thrombin-hirutonin-2 complex, the N- and C-terminal parts of the inhibitor are well or dered (except the C-terminal Gln-h65) while the central portion of the linker is partially disordered. The glycine analog in the P1′ position of hirutonin-2 assumes a conformation similar to that of the canonical form (Bode and Huber (1992) Eur. J. Biochem. 204 : 433-451) and supports the identification of the S1′ site as restricted by His57, Trp60D, Lys60F, and the Cys42-Cys58 disulfide bridge. The carbonyl oxygen of the P1 arginine residue is located in the oxyanion hole formed by the NH groups of Gly193 and Ser195, while the carbonyl carbon is positioned within a short distance, 2.8 Å, from the Oγ of Ser195. This resembles the conformation of the substrate-like inhibitors bound to other serine proteases. The N-terminal (D)Phe-pro-Arg fragment common to both inhibitors binds to thrombin in a fashion very similar to that of other inhibitors having this motif. The binding of the C-terminus of hirutonins to the fibrinogen-binding exosite is similar to that observed in hirudin and hirulog complexes. © 1993 Wiley-Liss, Inc.
    Additional Material: 9 Ill.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 0736-0266
    Keywords: Cobalt ; Chromium ; Nickel ; Total knee arthroplasty ; Total hip arthroplasty ; Prostheses, porous-coated ; Life and Medical Sciences
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Medicine
    Notes: Co, Cr, and Ni concentrations were determined by electrothermal atomic absorption spectrophotometry in serum and urine specimens collected from a group of 28 patients at intervals of from 1 day to 2.5 years after total knee or hip arthroplasty with porous-coated prostheses fabricated of Co-Cr alloy (ASTM F-75-82). Two control groups were also tested: (a) 42 healthy adults and (b) 16 orthopaedic patients after total knee or hip arthroplasty with porous-coated prostheses fabricated predominantly of Ti-Al-V alloy (ASTM F-136-84). All prostheses contained polyethylene components to avoid metal-to-metal contact. Mean Co concentrations in serum and urine were slightly increased in patients with Co-Cr knee implants at 6-120 weeks after surgery, compared with (a) preoperative values, (b) corresponding values in patients with Co-Cr hip implants, and (c) corresponding values in control patients with Ti-Al-V knee and hip prostheses. Substantially increased Co levels were observed in serum and urine of two patients at 7 weeks and 22 months postarthroplasty, associated with loosening of the prostheses; one of the patients also had elevated Cr levels in serum and urine. Although ASTM F-75-82 and F-136-84 alloys contain very little Ni (〈1.0 and 〈0.2% Ni, respectively, by wt), mean Ni concentrations in serum and urine were greatly increased at 1-2 days after implantation of Ti-Al-V and Co-Cr prostheses, diminishing by 2 weeks. The postoperative hypernickelemia and nickeluresis may reflect contamination of the operative field with Ni-containing particles from the drills, cutting jigs, and drilling jigs, or it may represent a previously unrecognized pathophysiological response to surgery.
    Additional Material: 2 Ill.
    Type of Medium: Electronic Resource
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