Schematic representation of the human hmgr gene and the human HMGRH and P. mevalonii HMGRP proteins. (a) The exon-intron structure of the human hmgr gene, which extends from position 74717172 to position 74741998 of the human genome; positions refer to the Ensembl Transcript ID for the human hmgr gene (ENST00000287936 ). The numbers indicate the start and end of each exon and intron and refer to the position in the human genome sequence, omitting the first three digits (747); exons are indicated as filled boxes. Exon 1 is an untranslated region (UTR), as are the last 1,758 nucleotides of exon 20. The exons encoding the membrane-anchor domain, a flexible linker region, and the catalytic domain are indicated below the gene structure. (b) Human HMGR protein (HMGRH) is comprised of three domains: the membrane anchor domain, a linker domain, and a catalytic domain; within the catalytic domain subdomains have been defined. The N domain connects the L domain to the linker domain; the L domain contains an HMG-CoA binding region; and the S domain functions to bind NADP(H). The cis-loop (indicated by an asterisk), a region present only in HMGRH but not HMGRP, connects the HMG-CoA-binding region with the NADPH-binding region. (c) The HMGRP protein does not contain the membrane-anchor domain or the linker domain but has a catalytic domain containing a large domain with an HMG-CoA binding region, and a small, NAD(H)-binding domain. The active site of HMG-CoA reductase is present at the homodimer interface between one monomer that binds the nicotinamide dinucleotide and a second monomer that binds HMG-CoA. The numbers underneath the diagrams in (b,c) denote amino acids (in the single-letter amino-acid code) that are implicated in catalysis; S872 of HMGRH is reversibly phosphorylated. At the extreme carboxyl terminus of each enzyme is a flap domain (approximately 50 amino acids in HMGRP and 25-30 amino acids in HMGRH) that closes over the active site during catalysis; the flap domain is indicated by shading in (b,c).