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  Structural and functional analyses of the human PDH complex suggest a "Division-of-Labor" mechanism by local E1 and E3 clusters.

Prajapati, S., Haselbach, D., Wittig, S., Patel, M. S., Chari, A., Schmidt, C., et al. (2019). Structural and functional analyses of the human PDH complex suggest a "Division-of-Labor" mechanism by local E1 and E3 clusters. Structure, 27(7), 1124-1136. doi:10.1016/j.str.2019.04.009.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0003-B0B9-5 Version Permalink: http://hdl.handle.net/21.11116/0000-0003-F3E1-C
Genre: Journal Article

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Prajapati, S., Author
Haselbach, D., Author
Wittig, S., Author
Patel, M. S., Author
Chari, A.1, Author              
Schmidt, C., Author
Stark, H.1, Author              
Tittmann, K., Author
Affiliations:
1Department of Structural Dynamics, MPI for Biophysical Chemistry, Max Planck Society, ou_2205645              

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Free keywords: crosslinking mass spectrometry; cryoelectron microscopy; enzymatic mechanism; multi-enzyme complex; native mass spectrometry; pyruvate dehydrogenase complex; stoichiometry; structure
 Abstract: The pseudo-atomic structural model of human pyruvate dehydrogenase complex (PDHc) core composed of full-length E2 and E3BP components, calculated from our cryoelectron microscopy-derived density maps at 6-Å resolution, is similar to those of prokaryotic E2 structures. The spatial organization of human PDHc components as evidenced by negative-staining electron microscopy and native mass spectrometry is not homogeneous, and entails the unanticipated formation of local clusters of E1:E2 and E3BP:E3 complexes. Such uneven, clustered organization translates into specific duties for E1-E2 clusters (oxidative decarboxylation and acetyl transfer) and E3BP-E3 clusters (regeneration of reduced lipoamide) corresponding to half-reactions of the PDHc catalytic cycle. The addition of substrate coenzyme A modulates the conformational landscape of PDHc, in particular of the lipoyl domains, extending the postulated multiple random coupling mechanism. The conformational and associated chemical landscapes of PDHc are thus not determined entirely stochastically, but are restrained and channeled through an asymmetric architecture and further modulated by substrate binding.

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Language(s): eng - English
 Dates: 2019-05-232019-07-02
 Publication Status: Published in print
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.str.2019.04.009
 Degree: -

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Title: Structure
Source Genre: Journal
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Pages: - Volume / Issue: 27 (7) Sequence Number: - Start / End Page: 1124 - 1136 Identifier: -