WNDP (Wilson's disease protein) is a copper-transporting ATPase that plays an essential role in human physiology. Mutations in WNDP result in copper accumulation in tissues and cause a severe hepato-neurological disorder known as Wilson's disease. Several mutations were surmised to affect the nucleotide binding and hydrolysis by WNDP; however, how the nucleotides bind to normal and mutated WNDP remains unknown. To aid such studies, we performed the molecular modelling of the spatial structure and dynamics of the ATP-binding domain of WNDP and its interactions with ATP. The three-dimensional models of this domain in two conformations were built using the X-ray structures of the Ca2+-ATPase in the E1 and E2 states. To study the functional aspects of the models, they were subjected to long-term molecular dynamics simulations in an explicit solvent; similar calculations were performed for the ATP-binding domain of Ca2+-ATPase. In both cases, we found large-scale motions that lead to significant changes of distances between several functionally important residues. The ATP docking revealed two possible modes of ATP binding: via adenosine buried in the cleft near residues H1069, R1151 and D1164, and via phosphate moiety ‘anchored’ by H-bonds with residues in the vicinity of catalytic D1027. Furthermore, interaction of ATP with both sites occurs if they are spatially close to each other. This may be achieved after relative domain motions of the ‘closure’ type observed in molecular dynamics simulations. The results provide a framework for analysis of disease mutations and for future mutagenesis studies.
Skip Nav Destination
Article navigation
August 2004
-
Cover Image
Cover Image
- PDF Icon PDF LinkFront Matter
- PDF Icon PDF LinkTable of Contents
- PDF Icon PDF LinkEditorial Board
Research Article|
August 10 2004
Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations
Roman G. EFREMOV;
Roman G. EFREMOV
1
*M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia
1To whom correspondence should be addressed (email efremov@nmr.ru).
Search for other works by this author on:
Yuri A. KOSINSKY;
Yuri A. KOSINSKY
*M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia
Search for other works by this author on:
Dmitry E. NOLDE;
Dmitry E. NOLDE
*M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia
Search for other works by this author on:
Ruslan TSIVKOVSKII;
Ruslan TSIVKOVSKII
†Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, U.S.A.
Search for other works by this author on:
Alexander S. ARSENIEV;
Alexander S. ARSENIEV
*M. M. Shemyakin & Yu. A. Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Ul. Miklukho-Maklaya, 16/10, Moscow V-437, 117997 GSP, Russia
Search for other works by this author on:
Svetlana LUTSENKO
Svetlana LUTSENKO
†Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, U.S.A.
Search for other works by this author on:
Publisher: Portland Press Ltd
Received:
March 01 2004
Revision Received:
May 06 2004
Accepted:
May 17 2004
Accepted Manuscript online:
May 17 2004
Online ISSN: 1470-8728
Print ISSN: 0264-6021
The Biochemical Society, London
2004
Biochem J (2004) 382 (1): 293–305.
Article history
Received:
March 01 2004
Revision Received:
May 06 2004
Accepted:
May 17 2004
Accepted Manuscript online:
May 17 2004
Citation
Roman G. EFREMOV, Yuri A. KOSINSKY, Dmitry E. NOLDE, Ruslan TSIVKOVSKII, Alexander S. ARSENIEV, Svetlana LUTSENKO; Molecular modelling of the nucleotide-binding domain of Wilson's disease protein: location of the ATP-binding site, domain dynamics and potential effects of the major disease mutations. Biochem J 15 August 2004; 382 (1): 293–305. doi: https://doi.org/10.1042/BJ20040326
Download citation file:
Sign in
Don't already have an account? Register
Sign in to your personal account
You could not be signed in. Please check your email address / username and password and try again.
Captcha Validation Error. Please try again.