4r51

Crystal complex structure of sp-Aspartate-Semialdehyde-Dehydrogenase with Nicotinamide Adenine dinucleotide phosphate and phthalic acid

spinqualitylabelsall models 4r51, resolution 1.81Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4r51 is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ACT, EDO, NA, NAP, PHT Related: 4r3n, 4r3w, 4r41, 4r4j Activity: Aspartate-semialdehyde dehydrogenase, with EC number 1.2.1.11 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [A5MTN0_STREE] Catalyzes the NADPH-dependent formation of L-aspartate-semialdehyde (L-ASA) by the reductive dephosphorylation of L-aspartyl-4-phosphate (By similarity).[HAMAP-Rule:MF_02121] Publication Abstract from PubMed The aspartate pathway is essential for the production of the amino acids required for protein synthesis and of the metabolites needed in bacterial development. This pathway also leads to the production of several classes of quorum-sensing molecules that can trigger virulence in certain microorganisms. The second enzyme in this pathway, aspartate beta-semialdehyde dehydrogenase (ASADH), is absolutely required for bacterial survival and has been targeted for the design of selective inhibitors. Fragment-library screening has identified a new set of inhibitors that, while they do not resemble the substrates for this reaction, have been shown to bind at the active site of ASADH. Structure-guided development of these lead compounds has produced moderate inhibitors of the target enzyme, with some selectivity observed between the Gram-negative and Gram-positive orthologs of ASADH. However, many of these inhibitor analogs and derivatives have not yet achieved the expected enhanced affinity. Structural characterization of these enzyme-inhibitor complexes has provided detailed explanations for the barriers that interfere with optimal binding. Despite binding in the same active-site region, significant changes are observed in the orientation of these bound inhibitors that are caused by relatively modest structural alterations. Taken together, these studies present a cautionary tale for issues that can arise in the systematic approach to the modification of lead compounds that are being used to develop potent inhibitors. A cautionary tale of structure-guided inhibitor development against an essential enzyme in the aspartate-biosynthetic pathway.,Pavlovsky AG, Thangavelu B, Bhansali P, Viola RE Acta Crystallogr D Biol Crystallogr. 2014 Dec 1;70(Pt 12):3244-52. doi:, 10.1107/S1399004714023979. Epub 2014 Nov 22. PMID:25478842 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aspartate-semialdehyde dehydrogenase

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