Cinnamoyl-CoA reductase (), systematically named cinnamaldehyde:NADP+ oxidoreductase (CoA-cinnamoylating) but commonly referred to by the acronym CCR, is an enzyme that catalyzes the reduction of a substituted cinnamoyl-CoA to its corresponding cinnamaldehyde, utilizing NADPH and H+ and releasing free CoA and NADP+ in the process. Common biologically relevant cinnamoyl-CoA substrates for CCR include p-coumaroyl-CoA and feruloyl-CoA, which are converted into p-coumaraldehyde and coniferaldehyde, respectively, though most CCRs show activity toward a variety of other substituted cinnamoyl-CoA's as well. Catalyzing the first committed step in monolignol biosynthesis, this enzyme plays a critical role in lignin formation, a process important in plants both for structural development and defense response. Structure The first confirmed CCR was isolated from soybean (Glycine max) in 1976. However, crystal structures have so far been reported for just three CCR homologs: Petunia x hybrida CCR1, Medicago truncatula CCR2, and Sorghum bicolor CCR1. While the enzyme crystallizes as an asymmetric dimer, it is thought to exist as a monomer in the cytoplasm, with each individual protein having a bilobal structure consisting of two domains surrounding a large, empty inner cleft for substrate binding. Typical CCRs have a molecular weight of around 36-38 kDa. The domain containing the enzyme's N-terminus consists of several alpha helices and six beta strands that, in addition to a seventh strand connected to the C-terminus side of the enzyme, form a parallel beta sheet structure known as a Rossmann fold. In CCR, this fold structure, a common motif amongst proteins, serves as a binding domain for NADPH. The second domain, which consists of several alpha helices, beta strands, and extended loops, is responsible for binding the cinnamoyl-CoA substrate. These two domains are situated in such a way that the binding sites for NADPH and cinnamoyl-CoA are positioned closely to one another at the lobes' interface. Though attempts to cocrystallize the enzyme with a bound cinnamoyl-CoA have thus far been unsuccessful, molecular docking studies indicate that the CoA segment of these molecules folds around to bind along the outer part of the inter-domain cleft, while the phenyl-containing portion of these substrates likely binds in the deepest part of the cleft. This inner part of the pocket contains several amino acids with nonpolar side chains necessary for stabilization of the hydrophobic phenyl ring in addition to a tyrosine residue important for hydrogen bond formation with the ring's 4-hydroxyl group. The particular identities of the nonpolar residues are believed