4COO

Crystal structure of human cystathionine beta-synthase (delta516-525) at 2.0 angstrom resolution

Summary for 4COO

• Entry DOI: 10.2210/pdb4coo/pdb
• Descriptor: CYSTATHIONINE BETA-SYNTHASE, PROTOPORPHYRIN IX CONTAINING FE, ACETATE ION, ... (8 entities in total)
• Functional Keywords: lyase, methionine cycle, metabolic pathway, allosteric regulation, serine metabolism
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm : P35520
• Total number of polymer chains: 2
• Total formula weight: 127123.27

Authors

McCorvie, T.J.,Kopec, J.,Vollamar, M.,Strain-Damerell, C.,Bushell, S.,Bradley, A.,Tallant, C.,Kiyani, W.,Froese, D.S.,Carpenter, E.S.,Burgess-Brown, N.,von Delft, F.,Arrowsmith, C.,Edwards, A.,Bountra, C.,Yue, W.W. (deposition date: 2014-01-29, release date: 2014-03-05, Last modification date: 2023-12-20)

Primary citation

Mccorvie, T.J.,Kopec, J.,Hyung, S.,Fitzpatrick, F.,Feng, X.,Termine, D.,Strain-Damerell, C.,Vollmar, M.,Fleming, J.,Janz, J.M.,Bulawa, C.,Yue, W.W.
Inter-Domain Communication of Human Cystathionine Beta Synthase: Structural Basis of S-Adenosyl-L-Methionine Activation.
J.Biol.Chem., 289:36018-, 2014

PubMed Abstract: Cystathionine β-synthase (CBS) is a key enzyme in sulfur metabolism, and its inherited deficiency causes homocystinuria. Mammalian CBS is modulated by the binding of S-adenosyl-l-methionine (AdoMet) to its regulatory domain, which activates its catalytic domain. To investigate the underlying mechanism, we performed x-ray crystallography, mutagenesis, and mass spectrometry (MS) on human CBS. The 1.7 Å structure of a AdoMet-bound CBS regulatory domain shows one AdoMet molecule per monomer, at the interface between two constituent modules (CBS-1, CBS-2). AdoMet binding is accompanied by a reorientation between the two modules, relative to the AdoMet-free basal state, to form interactions with AdoMet via residues verified by mutagenesis to be important for AdoMet binding (Phe(443), Asp(444), Gln(445), and Asp(538)) and for AdoMet-driven inter-domain communication (Phe(443), Asp(538)). The observed structural change is further supported by ion mobility MS, showing that as-purified CBS exists in two conformational populations, which converged to one in the presence of AdoMet. We therefore propose that AdoMet-induced conformational change alters the interface and arrangement between the catalytic and regulatory domains within the CBS oligomer, thereby increasing the accessibility of the enzyme active site for catalysis.

PubMed: 25336647
DOI: 10.1074/JBC.M114.610782

Experimental method

X-RAY DIFFRACTION (2 Å)