2BFC

Reactivity modulation of human branched-chain alpha-ketoacid dehydrogenase by an internal molecular switch

Summary for 2BFC

• Entry DOI: 10.2210/pdb2bfc/pdb
• Related: 1DTW 1OLS 1OLU 1OLX 1U5B 1V11 1V16 1V1M 1V1R 1WCI 1X7W 1X7X 1X7Y 1X7Z 1X80 2BEU 2BEV 2BEW 2BFB 2BFD 2BFE 2BFF
• Descriptor: 2-OXOISOVALERATE DEHYDROGENASE ALPHA SUBUNIT, 2-OXOISOVALERATE DEHYDROGENASE BETA SUBUNIT, POTASSIUM ION, ... (7 entities in total)
• Functional Keywords: oxidoreductase, oxidative decarboxylation, maple syrup urine disease, thiamine diphosphate, phosphorylation, conformational switch
• Biological source: HOMO SAPIENS (HUMAN); More
• Total number of polymer chains: 2
• Total formula weight: 84039.83

Authors

Machius, M.,Wynn, R.M.,Chuang, J.L.,Tomchick, D.R.,Brautigam, C.A.,Chuang, D.T. (deposition date: 2004-12-06, release date: 2006-02-16, Last modification date: 2023-12-13)

Primary citation

Machius, M.,Wynn, R.M.,Chuang, J.L.,Li, J.,Kluger, R.,Yu, D.,Tomchick, D.R.,Brautigam, C.A.,Chuang, D.T.
A Versatile Conformational Switch Regulates Reactivity in Human Branched-Chain Alpha-Ketoacid Dehydrogenase.
Structure, 14:287-, 2006

PubMed Abstract: The dehydrogenase/decarboxylase (E1b) component of the 4 MD human branched-chain alpha-ketoacid dehydrogenase complex (BCKDC) is a thiamin diphosphate (ThDP)-dependent enzyme. We have determined the crystal structures of E1b with ThDP bound intermediates after decarboxylation of alpha-ketoacids. We show that a key tyrosine residue in the E1b active site functions as a conformational switch to reduce the reactivity of the ThDP cofactor through interactions with its thiazolium ring. The intermediates do not assume the often-postulated enamine state, but likely a carbanion state. The carbanion presumably facilitates the second E1b-catalyzed reaction, involving the transfer of an acyl moiety from the intermediate to a lipoic acid prosthetic group in the transacylase (E2b) component of the BCKDC. The tyrosine switch further remodels an E1b loop region to promote E1b binding to E2b. Our results illustrate the versatility of the tyrosine switch in coordinating the catalytic events in E1b by modulating the reactivity of reaction intermediates.

PubMed: 16472748
DOI: 10.1016/J.STR.2005.10.009

Experimental method

X-RAY DIFFRACTION (1.64 Å)