8rkq
Structure of human DELTA-1-PYRROLINE-5-CARBOXYLATE DEHYDROGENASE (ALDH4A1) complexed with the molecular tweezer CLR01
Structural highlights
DiseaseAL4A1_HUMAN Hyperprolinemia type 2. The disease is caused by mutations affecting the gene represented in this entry. FunctionAL4A1_HUMAN Irreversible conversion of delta-1-pyrroline-5-carboxylate (P5C), derived either from proline or ornithine, to glutamate. This is a necessary step in the pathway interconnecting the urea and tricarboxylic acid cycles. The preferred substrate is glutamic gamma-semialdehyde, other substrates include succinic, glutaric and adipic semialdehydes.[1] Publication Abstract from PubMedTo understand the biological relevance and mode of action of artificial protein ligands, crystal structures with their protein targets are essential. Here, we describe and investigate all known crystal structures that contain a so-called "molecular tweezer" or one of its derivatives with an attached natural ligand on the respective target protein. The aromatic ring system of these compounds is able to include lysine and arginine side chains, supported by one or two phosphate groups that are attached to the half-moon-shaped molecule. Due to their marked preference for basic amino acids and the fully reversible binding mode, molecular tweezers are able to counteract pathologic protein aggregation and are currently being developed as disease-modifying therapies against neurodegenerative diseases such as Alzheimer's and Parkinson's disease. We analyzed the corresponding crystal structures with 14-3-3 proteins in complex with mono- and diphosphate tweezers. Furthermore, we solved crystal structures of two different tweezer variants in complex with the enzyme Delta(1)-Pyrroline-5-carboxyl-dehydrogenase (P5CDH) and found that the tweezers are bound to a lysine and methionine side chain, respectively. The different binding modes and their implications for affinity and specificity are discussed, as well as the general problems in crystallizing protein complexes with artificial ligands. How Do Molecular Tweezers Bind to Proteins? Lessons from X-ray Crystallography.,Porfetye AT, Stege P, Rebollido-Rios R, Hoffmann D, Schrader T, Vetter IR Molecules. 2024 Apr 12;29(8):1764. doi: 10.3390/molecules29081764. PMID:38675584[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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