4pcu

Crystal structure of delta516-525 E201S human cystathionine beta-synthase with AdoMet

spinqualitylabelsall models 4pcu, resolution 3.58Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4pcu is a 2 chain structure. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: HEM, PLP, SAM Related: 4l0d, 4l3v, 4l28, 4l27 Activity: Cystathionine beta-synthase, with EC number 4.2.1.22 Resources: FirstGlance, OCA, RCSB, PDBsum Disease [CBS_HUMAN] Defects in CBS are the cause of cystathionine beta-synthase deficiency (CBSD) [MIM:236200]. CBSD is an enzymatic deficiency resulting in altered sulfur metabolism and homocystinuria. The clinical features of untreated homocystinuria due to CBS deficiency include myopia, ectopia lentis, mental retardation, skeletal anomalies resembling Marfan syndrome, and thromboembolic events. Light skin and hair can also be present. Biochemical features include increased urinary homocystine and methionine. Function [CBS_HUMAN] Only known pyridoxal phosphate-dependent enzyme that contains heme. Important regulator of hydrogen sulfide, especially in the brain, utilizing cysteine instead of serine to catalyze the formation of hydrogen sulfide. Hydrogen sulfide is a gastratransmitter with signaling and cytoprotective effects such as acting as a neuromodulator in the brain to protect neurons against hypoxic injury (By similarity). Publication Abstract from PubMed Cystathionine beta-synthase (CBS) is a heme-dependent and pyridoxal-5'-phosphate-dependent protein that controls the flux of sulfur from methionine to cysteine, a precursor of glutathione, taurine, and H2S. Deficiency of CBS activity causes homocystinuria, the most frequent disorder of sulfur amino acid metabolism. In contrast to CBSs from lower organisms, human CBS (hCBS) is allosterically activated by S-adenosylmethionine (AdoMet), which binds to the regulatory domain and triggers a conformational change that allows the protein to progress from the basal toward the activated state. The structural basis of the underlying molecular mechanism has remained elusive so far. Here, we present the structure of hCBS with bound AdoMet, revealing the activated conformation of the human enzyme. Binding of AdoMet triggers a conformational change in the Bateman module of the regulatory domain that favors its association with a Bateman module of the complementary subunit to form an antiparallel CBS module. Such an arrangement is very similar to that found in the constitutively activated insect CBS. In the presence of AdoMet, the autoinhibition exerted by the regulatory region is eliminated, allowing for improved access of substrates to the catalytic pocket. Based on the availability of both the basal and the activated structures, we discuss the mechanism of hCBS activation by AdoMet and the properties of the AdoMet binding site, as well as the responsiveness of the enzyme to its allosteric regulator. The structure described herein paves the way for the rational design of compounds modulating hCBS activity and thus transsulfuration, redox status, and H2S biogenesis. Structural insight into the molecular mechanism of allosteric activation of human cystathionine beta-synthase by S-adenosylmethionine.,Ereno-Orbea J, Majtan T, Oyenarte I, Kraus JP, Martinez-Cruz LA Proc Natl Acad Sci U S A. 2014 Sep 16;111(37):E3845-52. doi:, 10.1073/pnas.1414545111. Epub 2014 Sep 2. PMID:25197074 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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