4oca
From Proteopedia
Cryatal structure of ArnB K188A complexted with PLP and UDP-Ara4N
Structural highlights
Function[F5ZUF5_SALTU] Catalyzes the conversion of UDP-4-keto-arabinose (UDP-Ara4O) to UDP-4-amino-4-deoxy-L-arabinose (UDP-L-Ara4N). The modified arabinose is attached to lipid A and is required for resistance to polymyxin and cationic antimicrobial peptides (By similarity).[HAMAP-Rule:MF_01167][SAAS:SAAS022850_004_033570] Publication Abstract from PubMedCationic Antimicrobial Peptides (CAMPs) represent a first line of defense against bacterial colonization. When fighting Gram-negative bacteria, CAMPs initially interact electrostatically with the negatively charged phosphate groups in lipid A and are thought to kill bacteria by disrupting their membrane integrity. However, many human pathogens, including Salmonella and Pseudomonas , have evolved lipid A modification mechanisms that result in resistance to CAMPs and related antibiotics such as Colistin. The addition of 4-amino-4-deoxy-l-Arabinose (Ara4N) to a phosphate group in lipid A is one such modification, frequently found in Pseudomonas isolated from cystic fibrosis patients. The pathway for biosynthesis of Ara4N-lipid A requires conversion of UDP-Glucuronic acid into UDP-Ara4N and subsequent transfer of the amino-sugar to lipid A. ArnB is a pyridoxal-phosphate (PLP) dependent transaminase that catalyzes a crucial step in the pathway: synthesis of UDP-Ara4N from UDP-4-keto-pentose. Here we present the 2.3 A resolution crystal structure of an active site mutant of ArnB (K188A) in complex with the reaction intermediate aldimine formed by UDP-Ara4N and PLP. The sugar-nucleotide binding site is in a cleft between the subunits of the ArnB dimer with the uracil buried at the interface and the UDP ribose and phosphate groups exposed to the solvent. The Ara4N moiety is found in the (4)C1 conformation and its positioning, stabilized by interactions with both the protein and cofactor, is compatible with catalysis. The structure suggests strategies for the development of specific inhibitors that may prove useful in the treatment of resistant bacteria such as Pseudomonas found in cystic fibrosis patients. Structural Basis for Substrate Specificity in ArnB. A Key Enzyme in the Polymyxin Resistance Pathway of Gram-Negative Bacteria.,Lee M, Sousa MC Biochemistry. 2014 Feb 4;53(4):796-805. doi: 10.1021/bi4015677. Epub 2014 Jan 24. PMID:24460375[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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