Supplementary Figure 3: Structural comparison between the TBD tri-Trp pockets. | Nature Structural & Molecular Biology

Supplementary Figure 3: Structural comparison between the TBD tri-Trp pockets.

From: Structure of the human Cereblon–DDB1–lenalidomide complex reveals basis for responsiveness to thalidomide analogs

Supplementary Figure 3

(a) Comparison between thalidomide bound and apo CRBN showing that the binding pocket is formed in the absence of IMiD. The thalidomide bound form is shown with carbons in cyan/yellow and the apo form is shown with carbons in grey. Comparison of the Tri-Trp hole with related modified amine-binding sites. (b), The trimethyl lysine-binding pocket of HP1 chromodomain (grey). The pocket is composed of one Trp and two Tyr residues for binding to histone H3 trimethylated Lys. HP1 is a member of the royal family group of proteins which possess an aromatic methylated lysine and/or arginine-binding pocket. The binding pocket is usually composed of two to four aromatic residues, providing electrostatic and hydrophobic contacts to accommodate the insertion of methylated ligand of the binding partner proteins. The pocket of BPTF PHD finger is composed of one Trp and three Tyr residues for binding to histone H3 trimethylated Lys42(not shown). (c) The dimethyl lysine-binding pocket of 53BP1 Tudor domain (grey) of the royal family. The pocket is formed by one Trp, two Tyr, one Phe and one Asp residue (green), forming an aromatic environment with a salt bridge (dotted line) between the Lys dimethyl amino group and the Asp side-chain carboxyl group. (d) The acetyl lysine-binding pocket of GCN5 bromodomain (grey). The pocket is formed by a mixture of aromatic (three Tyr and one Phe), aliphatic (Val and Pro) and Asn residues (green). The acetyl group is recognized by formation of a direct hydrogen bond to Asn and water-mediated hydrogen bonds (broken lines). (e) Overlay of the tryptophan box forming the betaine-binding pocket of E. coli ProX (green) on the Tri-Trp hole ofpocket of the CRBN TBDMBS domain (cyan). Three Trp residues are labeled. S-thalidomide (SThal, yellow) bound to the Tri-Trp hole pocket is also shown. (f) The betaine-binding site of E. coli ProX (grey). The tryptophan box formed by three conserved Trp and one Tyr residue (green) creates an aromatic environment for binding to betaine (N,N,Ntrimethyl glycine) by cation-pi interactions and van der Waals contacts. In contrast to the CRBN Tri-Trp pocket, the ProX betaine-binding site is located at the cleft between two domains, and the Trp residues of the tryptophan box and the bound betaine are completely occluded inside the protein. (g) As in f, but for the betaine-binding pocket of E. coli BetP (grey). The Trp residues and the bound betaine are completely occluded inside the protein as in ProX.

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