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Ligand-induced conformational changes and a mechanism for domain closure in Aspergillus nidulans dehydroquinate synthase

Lookup NU author(s): Dr Heather Lamb, Professor Alastair Hawkins


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In order to investigate systematically substrate and cofactor-induced conformational changes in the enzyme dehydroquinate synthase (DHQS), eight structures representing a series of differently liganded states have been determined in a total of six crystal forms. DHQS in the absence of the substrate analogue carbaphosphonate, either unliganded or in the presence of NAD or ADP, is in an open form where a relative rotation of 11-13° between N and C-terminal domains occurs. Analysis of torsion angle difference plots between sets of structures reveals eight rearrangements that appear relevant to domain closure and a further six related to crystal packing. Overlapping 21 different copies of the individual N and C-terminal DHQS domains further reveals a series of pivot points about which these movements occur and illustrates the way in which widely separated secondary structure elements are mechanically inter-linked to form "composite elements", which propagate structural changes across large distances. This analysis has provided insight into the basis of DHQS ligand-initiated domain closure and gives rise to the proposal of an ordered sequence of events involving substrate binding, and local rearrangements within the active site that are propagated to the hinge regions, leading to closure of the active-site cleft. © 2003 Elsevier Science Ltd. All rights reserved.

Publication metadata

Author(s): Nichols CE, Ren J, Lamb HK, Hawkins AR, Stammers DK

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Biology

Year: 2003

Volume: 327

Issue: 1

Pages: 129-144

ISSN (print): 0022-2836

ISSN (electronic): 1089-8638

Publisher: Academic Press


DOI: 10.1016/S0022-2836(03)00086-X

PubMed id: 12614613


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