9hif | pdb_00009hif

Crystal Structure of Human cystathionine beta-synthase variant R336C

spinqualitylabelsall models 9hif, resolution 3.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 9hif is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.65Å Ligands: HEM, LLP Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT 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 pyridoxal-phosphate (PLP)-dependent enzyme essential for the reverse transsulfuration pathway, where homocysteine and serine combine to form cystathionine, the immediate precursor of cysteine. Mutations in the CBS gene cause homocystinuria, a disorder associated with intellectual disability, multisystem complications, and reduced life expectancy. The CBS p.R336C mutation, linked to severe pyridoxine non-responsiveness, results in reduced enzyme activity, previously attributed to protein instability and weakened substrate and PLP binding. To clarify the effects of the pathological R336C mutation, we performed biochemical, biophysical, and crystallographic analyses, as well as molecular dynamics simulations. Our findings show that the R336C mutation minimally impacts the structural environment around residue 336, does not cause enzyme misfolding, and does not impair the binding of PLP or the allosteric activator S-adenosylmethionine (AdoMet) binding. Instead, the mutation induces subtle reorientations in nearby hydrophobic residues, including F185 and Y381, altering intramolecular contacts that perturb the interaction between asparagine 149 and the O3 oxygen of PLP. This alteration is known to potentially shift the tautomeric equilibrium of the PLP Schiff base from its catalytically active ketoenamine form to the inactive enolimine form, which aligns with the reduced activity of the R336C variant. Additionally, the R336C mutation disrupts intermolecular contacts between the catalytic core and Bateman module, altering the Bateman module's intrinsic mobility in the enzyme's basal state and potentially affecting the cavity opening required for catalysis. Importantly, the R336C variant retains the native enzyme's ability to assemble into polymeric chains in crystals, preserving its filament formation capacity. The disease-linked R336C mutation in cystathionine beta-synthase disrupts communication with the PLP cofactor, yet maintains the enzyme's overall structural integrity.,Conter C, Nunez-Franco R, Al-Sadeq DW, Fernandez-Rodriguez C, Goikoetxea-Usandizaga N, Nasrallah GK, Nomikos M, Martinez-Chantar ML, Astegno A, Jimenez-Oses G, Martinez-Cruz LA FEBS J. 2025 May 6. doi: 10.1111/febs.70116. PMID:40327797 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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