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  • Hydrophobic and Hydrophilic Interactions  (2)
  • 2010-2014  (2)
  • 1935-1939
  • 2011  (2)
  • 1
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    N2O binding at a [4Cu:2S] copper-sulphur cluster in nitrous oxide reductase (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-08-16
    Description: Nitrous oxide (N(2)O) is generated by natural and anthropogenic processes and has a critical role in environmental chemistry. It has an ozone-depleting potential similar to that of hydrochlorofluorocarbons as well as a global warming potential exceeding that of CO(2) 300-fold. In bacterial denitrification, N(2)O is reduced to N(2) by the copper-dependent nitrous oxide reductase (N(2)OR). This enzyme carries the mixed-valent Cu(A) centre and the unique, tetranuclear Cu(Z) site. Previous structural data were obtained with enzyme isolated in the presence of air that is catalytically inactive without prior reduction. Its Cu(Z) site was described as a [4Cu:S] centre, and the substrate-binding mode and reduction mechanism remained elusive. Here we report the structure of purple N(2)OR from Pseudomonas stutzeri, handled under the exclusion of dioxygen, and locate the substrate in N(2)O-pressurized crystals. The active Cu(Z) cluster contains two sulphur atoms, yielding a [4Cu:2S] stoichiometry; and N(2)O bound side-on at Cu(Z), in close proximity to Cu(A). With the substrate located between the two clusters, electrons are transferred directly from Cu(A) to N(2)O, which is activated by side-on binding in a specific binding pocket on the face of the [4Cu:2S] centre. These results reconcile a multitude of available biochemical data on N(2)OR that could not be explained by earlier structures, and outline a mechanistic pathway in which both metal centres and the intervening protein act in concert to achieve catalysis. This structure represents the first direct observation, to our knowledge, of N(2)O bound to its reductase, and sheds light on the functionality of metalloenzymes that activate inert small-molecule substrates. The principle of using distinct clusters for substrate activation and for reduction may be relevant for similar systems, in particular nitrogen-fixing nitrogenase.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Pomowski, Anja -- Zumft, Walter G -- Kroneck, Peter M H -- Einsle, Oliver -- England -- Nature. 2011 Aug 14;477(7363):234-7. doi: 10.1038/nature10332.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Lehrstuhl fur Biochemie, Institut fur organische Chemie und Biochemie, Albert-Ludwigs-Universitat Freiburg, Albertstr. 21, 79104 Freiburg, Germany.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21841804" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Copper/chemistry/*metabolism ; Crystallography, X-Ray ; Electrons ; Hydrophobic and Hydrophilic Interactions ; Models, Molecular ; Nitrous Oxide/chemistry/*metabolism ; Oxidoreductases/*chemistry/*metabolism ; Protein Binding ; Protein Conformation ; Protein Multimerization ; Pseudomonas stutzeri/*enzymology ; Sulfur/chemistry/*metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Structure of the human histamine H1 receptor complex with doxepin (2011)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2011-06-24
    Description: The biogenic amine histamine is an important pharmacological mediator involved in pathophysiological processes such as allergies and inflammations. Histamine H(1) receptor (H(1)R) antagonists are very effective drugs alleviating the symptoms of allergic reactions. Here we show the crystal structure of the H(1)R complex with doxepin, a first-generation H(1)R antagonist. Doxepin sits deep in the ligand-binding pocket and directly interacts with Trp 428(6.48), a highly conserved key residue in G-protein-coupled-receptor activation. This well-conserved pocket with mostly hydrophobic nature contributes to the low selectivity of the first-generation compounds. The pocket is associated with an anion-binding region occupied by a phosphate ion. Docking of various second-generation H(1)R antagonists reveals that the unique carboxyl group present in this class of compounds interacts with Lys 191(5.39) and/or Lys 179(ECL2), both of which form part of the anion-binding region. This region is not conserved in other aminergic receptors, demonstrating how minor differences in receptors lead to pronounced selectivity differences with small molecules. Our study sheds light on the molecular basis of H(1)R antagonist specificity against H(1)R.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131495/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3131495/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shimamura, Tatsuro -- Shiroishi, Mitsunori -- Weyand, Simone -- Tsujimoto, Hirokazu -- Winter, Graeme -- Katritch, Vsevolod -- Abagyan, Ruben -- Cherezov, Vadim -- Liu, Wei -- Han, Gye Won -- Kobayashi, Takuya -- Stevens, Raymond C -- Iwata, So -- 062164/ Z/00/Z/Wellcome Trust/United Kingdom -- BB/G023425/1/Biotechnology and Biological Sciences Research Council/United Kingdom -- P50 GM073197/GM/NIGMS NIH HHS/ -- P50 GM073197-07/GM/NIGMS NIH HHS/ -- R01 GM071872/GM/NIGMS NIH HHS/ -- R01 GM071872-02/GM/NIGMS NIH HHS/ -- R01 GM071872-08/GM/NIGMS NIH HHS/ -- R01 GM089857/GM/NIGMS NIH HHS/ -- U54 GM094618/GM/NIGMS NIH HHS/ -- U54 GM094618-01/GM/NIGMS NIH HHS/ -- England -- Nature. 2011 Jun 22;475(7354):65-70. doi: 10.1038/nature10236.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Human Receptor Crystallography Project, ERATO, Japan Science and Technology Agency, Kyoto 606-8501, Japan.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/21697825" target="_blank"〉PubMed〈/a〉
    Keywords: Binding Sites ; Crystallography, X-Ray ; Doxepin/chemistry/*metabolism ; Histamine Antagonists/chemistry/*metabolism ; Humans ; Hydrophobic and Hydrophilic Interactions ; Isomerism ; Ligands ; Models, Molecular ; Phosphates/chemistry/metabolism ; Protein Binding ; Protein Conformation ; Receptors, Adrenergic, beta-2/chemistry ; Receptors, Dopamine D3/chemistry ; Receptors, Histamine H1/*chemistry/*metabolism ; Substrate Specificity
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
    Location Call Number Expected Availability
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