4j3b

A naturally variable residue in the S1 subsite of M1-family aminopeptidases modulates catalytic properties and promotes functional specialization

spinqualitylabelsall models 4j3b, resolution 2.20Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4j3b is a 1 chain structure with sequence from Plasmodium falciparum FcB1/Columbia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: ARG, MG, ZN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function AMP1_PLAFQ Displays aminopeptidase activity with a broad substrate specificity. Preferentially hydrolyzes L-Lys-AMC but also shows strong activity against L-Ala-AMC, L-Arg-AMC and L-Leu-AMC. Publication Abstract from PubMed M1-family metallo-aminopeptidases fulfill a wide range of critical and in some cases medically relevant roles in humans and human pathogens. The specificity of M1-aminopeptidases is dominated by the interaction of the well-defined S1 subsite with the sidechain of the first (P1) residue of the substrate and can vary widely. Extensive natural variation occurs at one of the residues that contributes to formation of the cylindrical S1 subsite. We investigated whether this natural variation contributes to diversity in S1 subsite specificity. Effects of eleven substitutions of the S1 subsite residue valine 459 in the Plasmodium falciparum aminopeptidase PfA-M1 and of three substitutions of the homologous residue methionine 260 in Escherichia coli PepN were characterized. Many of these substitutions altered steady-state kinetic parameters for dipeptide hydrolysis and remodeled S1 subsite specificity. The most dramatic change in specificity resulted from substitution with proline, which collapsed S1 subsite specificity such that only substrates with P1-Arg, -Lys or -Met were appreciably hydrolyzed. The structure of PfA-M1 V459P revealed that the proline substitution induced a local conformational change in the polypeptide backbone that resulted in a narrowed S1 subsite. The restricted specificity and active site backbone conformation of PfA-M1 V459P mirrored those of endoplasmic reticulum aminopeptidase 2, a human enzyme with proline in the variable S1 subsite position. Our results provide compelling evidence that changes in the variable residue in the S1 subsite of M1-aminopeptidases have facilitated the evolution of new specificities and ultimately novel functions for this important class of enzymes. A naturally variable residue in the S1 subsite of M1-family aminopeptidases modulates catalytic properties and promotes functional specialization.,Dalal S, Ragheb DR, Schubot FD, Klemba M J Biol Chem. 2013 Jul 29. PMID:23897806 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Aminopeptidase 3D structures

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