Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase

Miller, Bradley R.; Kung, Yan

doi:10.1021/acs.biochem.7b00999

Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase

Journal Article · Mon Dec 11 00:00:00 EST 2017 · Biochemistry

DOI:https://doi.org/10.1021/acs.biochem.7b00999· OSTI ID:1424766

Miller, Bradley R. ^[1]; ^[1]

Bryn Mawr College, PA (United States)

The key mevalonate pathway enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (HMGR) uses the cofactor NAD(P)H to reduce HMG-CoA to mevalonate in the production of countless metabolites and natural products. Although inhibition of HMGR by statin drugs is well-understood, several mechanistic details of HMGR catalysis remain unresolved, and the structural basis for the wide range of cofactor specificity for either NADH or NADPH among HMGRs from different organisms is also unknown. Here, we present crystal structures of HMGR from Streptococcus pneumoniae (SpHMGR) alongside kinetic data of the enzyme’s cofactor preferences. Furthermore, our structure of SpHMGR bound with its kinetically preferred NADPH cofactor suggests how NADPH-specific binding and recognition are achieved. In addition, our structure of HMG-CoA-bound SpHMGR reveals large, previously unknown conformational domain movements that may control HMGR substrate binding and enable cofactor exchange without intermediate release during the catalytic cycle. Taken together, this work provides critical new insights into both the HMGR reaction mechanism and the structural basis of cofactor specificity.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH-ORIP HE; National Inst. of Health; USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22). Scientific User Facilities Division

Grant/Contract Number:: AC02-06CH11357

OSTI ID:: 1424766

Journal Information:: Biochemistry, Journal Name: Biochemistry Journal Issue: 5 Vol. 57; ISSN 0006-2960

Publisher:: American Chemical Society (ACS)Copyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding Costa, Clauber Henrique Souza; Oliveira, Amanda Ruslana Santana; dos Santos, Alberto M. Journal of Biomolecular Structure and Dynamics, Vol. 37, Issue 16 https://doi.org/10.1080/07391102.2018.1549508	journal	November 2018
Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding Costa, Clauber Henrique Souza; Oliveira, Amanda Ruslana Santana; Santos, Alberto M. Dos Taylor & Francis https://doi.org/10.6084/m9.figshare.7638107	text	January 2019
Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding Costa, Clauber Henrique Souza; Oliveira, Amanda Ruslana Santana; Santos, Alberto M. Dos Taylor & Francis https://doi.org/10.6084/m9.figshare.7638107.v1	text	January 2019
Computational study of conformational changes in human 3-hydroxy-3-methylglutaryl coenzyme reductase induced by substrate binding Costa, Clauber Henrique Souza; Oliveira, Amanda Ruslana Santana; Santos, Alberto M. Dos Taylor & Francis https://doi.org/10.6084/m9.figshare.7638107.v2	text	January 2019

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Structural Features and Domain Movements Controlling Substrate Binding and Cofactor Specificity in Class II HMG-CoA Reductase

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