7thn

Crystal structure of PigI trapped with PigG using a proline adenosine vinylsulfonamide inhibitor

spinqualitylabelsall models 7thn, resolution 1.60Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 7thn is a 2 chain structure with sequence from Serratia sp. ATCC 39006. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: AZI, GOL, I5M, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PIGI_SERS3 Involved in the biosynthesis of 4-methoxy-2,2'-bipyrrole-5-carbaldehyde (MBC), one of the terminal products involved in the biosynthesis of the red antibiotic prodigiosin (Pig) (PubMed:15853884, PubMed:17002325). Catalyzes the conversion of L-proline to L-prolyl-AMP and the transfer of the L-prolyl group to acyl carrier protein PigG (PubMed:17002325). Publication Abstract from PubMed Non-ribosomal peptides play a critical role in the clinic as therapeutic agents. To access more chemically diverse therapeutics, non-ribosomal peptide synthetases (NRPSs) have been targeted for engineering through combinatorial biosynthesis; however, this has been met with limited success in part due to the lack of proper protein-protein interactions between non-cognate proteins. Herein, we report our use of chemical biology to enable X-ray crystallography, molecular dynamics (MD) simulations, and biochemical studies to elucidate binding specificities between peptidyl carrier proteins (PCPs) and adenylation (A) domains. Specifically, we determined X-ray crystal structures of a type II PCP crosslinked to its cognate A domain, PigG and PigI, and of PigG crosslinked to a non-cognate PigI homologue, PltF. The crosslinked PCP-A domain structures possess large protein-protein interfaces that predominantly feature hydrophobic interactions, with specific electrostatic interactions that orient the substrate for active site delivery. MD simulations of the PCP-A domain complexes and unbound PCP structures provide a dynamical evaluation of the transient interactions formed at PCP-A domain interfaces, which confirm the previously hypothesized role of a PCP loop as a crucial recognition element. Finally, we demonstrate that the interfacial interactions at the PCP loop 1 region can be modified to control PCP binding specificity through gain-of-function mutations. This work suggests that loop conformational preferences and dynamism account for improved shape complementary in the PCP-A domain interactions. Ultimately, these studies show how crystallographic, biochemical, and computational methods can be used to rationally re-engineer NRPSs for non-cognate interactions. Essential Role of Loop Dynamics in Type II NRPS Biomolecular Recognition.,Corpuz JC, Patel A, Davis TD, Podust LM, McCammon JA, Burkart MD ACS Chem Biol. 2022 Oct 21;17(10):2890-2898. doi: 10.1021/acschembio.2c00523. , Epub 2022 Sep 29. PMID:36173802 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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