7qyh

Structure of plasmepsin II in complex with 2-aminoquinazolin-4(3H)-one based open-flap inhibitor

spinqualitylabelsall models 7qyh, resolution 3.33Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7qyh is a 4 chain structure with sequence from Plasmodium falciparum 3D7. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.33Å Ligands: I0J Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PLM2_PLAF7 During the asexual blood stage, participates in initial cleavage of native host hemoglobin (Hb) resulting in Hb denaturation (PubMed:29943906). May cleave preferentially denatured hemoglobin that has been cleaved by PMI (By similarity). Digestion of host Hb is an essential step which provides the parasite with amino acids for protein synthesis, and regulates osmolarity (Probable).[UniProtKB:P46925] Publication Abstract from PubMed Selectivity is a major issue in the development of drugs targeting pathogen aspartic proteases. Here, we explore the selectivity-determining factors by studying specifically designed malaria aspartic protease (plasmepsin) open-flap inhibitors. Metadynamics simulations are used to uncover the complex binding/unbinding pathways of these inhibitors and describe the critical transition states in atomistic resolution. The simulation results are compared with experimentally determined enzymatic activities. Our findings demonstrate that plasmepsin inhibitor selectivity can be achieved by targeting the flap loop with hydrophobic substituents that enable ligand binding under the flap loop, as such a behavior is not observed for several other aspartic proteases. The ability to estimate the selectivity of compounds before they are synthesized is of considerable importance in drug design; therefore, we expect that our approach will be useful in selective inhibitor designs against not only aspartic proteases but also other enzyme classes. Exploring Aspartic Protease Inhibitor Binding to Design Selective Antimalarials.,Bobrovs R, Basens EE, Drunka L, Kanepe I, Matisone S, Velins KK, Andrianov V, Leitis G, Zelencova-Gopejenko D, Rasina D, Jirgensons A, Jaudzems K J Chem Inf Model. 2022 Jul 11;62(13):3263-3273. doi: 10.1021/acs.jcim.2c00422. , Epub 2022 Jun 17. PMID:35712895 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Plasmepsin

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