2w8w

N100Y SPT with PLP-ser

spinqualitylabelsall models 2w8w, resolution 2.14Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 2w8w is a 1 chain structure with sequence from Sphingomonas paucimobilis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.14Å Ligands: PLS Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function SPT_SPHPI Catalyzes the condensation of L-serine with palmitoyl-CoA (hexadecanoyl-CoA) to produce 3-oxosphinganine (PubMed:11279212, PubMed:17557831, PubMed:17559874, PubMed:19376777). Exhibits a broad substrate specificity concerning the chain length and the degree of unsaturation of acyl-CoA (PubMed:11279212, PubMed:19376777). Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed Sphingolipid biosynthesis begins with the condensation of L-serine and palmitoyl-CoA catalyzed by the PLP-dependent enzyme serine palmitoyltransferase (SPT). Mutations in human SPT cause hereditary sensory autonomic neuropathy type 1, a disease characterized by loss of feeling in extremities and severe pain. The human enzyme is a membrane-bound hetereodimer, and the most common mutations are located in the enzymatically incompetent monomer, suggesting a "dominant" or regulatory effect. The molecular basis of how these mutations perturb SPT activity is subtle and is not simply loss of activity. To further explore the structure and mechanism of SPT, we have studied the homodimeric bacterial enzyme from Sphingomonas paucimobilis. We have analyzed two mutants (N100Y and N100W) engineered to mimic the mutations seen in hereditary sensory autonomic neuropathy type 1 as well as a third mutant N100C designed to mimic the wild-type human SPT. The N100C mutant appears fully active, whereas both N100Y and N100W are significantly compromised. The structures of the holoenzymes reveal differences around the active site and in neighboring secondary structure that transmit across the dimeric interface in both N100Y and N100W. Comparison of the l-Ser external aldimine structures of both native and N100Y reveals significant differences that hinder the movement of a catalytically important Arg(378) residue into the active site. Spectroscopic analysis confirms that both N100Y and N100W mutants subtly affect the chemistry of the PLP. Furthermore, the N100Y and R378A mutants appear less able to stabilize a quinonoid intermediate. These data provide the first experimental insight into how the most common disease-associated mutations of human SPT may lead to perturbation of enzyme activity. The external aldimine form of serine palmitoyltransferase: structural, kinetic, and spectroscopic analysis of the wild-type enzyme and HSAN1 mutant mimics.,Raman MC, Johnson KA, Yard BA, Lowther J, Carter LG, Naismith JH, Campopiano DJ J Biol Chem. 2009 Jun 19;284(25):17328-39. Epub 2009 Apr 17. PMID:19376777 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Serine palmitoyltransferase 3D structures

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