TY - JOUR
T1 - Three-dimensional structure of human monoamine oxidase A (MAO A)
T2 - Relation to the structures of rat MAO A and human MAO B
AU - De Colibus, Luigi
AU - Li, Min
AU - Binda, Claudia
AU - Lustig, Ariel
AU - Edmondson, Dale E.
AU - Mattevi, Andrea
PY - 2005/9/6
Y1 - 2005/9/6
N2 - The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO B), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic behavior of a monomeric form rather than the dimeric form of hMAO B and rat MAO A. hMAO A's active site consists of a single hydrophobic cavity of ≈550 Å3, which is smaller than that determined from the structure of deprenyl-inhibited hMAO B (≈700 Å3) but larger than that of rat MAO A (≈450 Å3). An important component of the active site structure of hMAO A is the loop conformation of residues 210-216, which differs from that of hMAO B and rat MAO A. The origin of this structural alteration is suggested to result from long-range interactions in the monomeric form of the enzyme. In addition to serving as a basis for the development of hMAO A specific inhibitors, these data support the proposal that hMAO A involves a change from the dimeric to the monomeric form through a Glu-151 → Lys mutation that is specific of hMAO A [Andrès, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum. Genet. 115, 377-386]. These considerations put into question the use of MAO A from nonhuman sources in drug development for use in humans.
AB - The three-dimensional structure of recombinant human monoamine oxidase A (hMAO A) as its clorgyline-inhibited adduct is described. Although the chain-fold of hMAO A is similar to that of rat MAO A and human MAO B (hMAO B), hMAO A is unique in that it crystallizes as a monomer and exhibits the solution hydrodynamic behavior of a monomeric form rather than the dimeric form of hMAO B and rat MAO A. hMAO A's active site consists of a single hydrophobic cavity of ≈550 Å3, which is smaller than that determined from the structure of deprenyl-inhibited hMAO B (≈700 Å3) but larger than that of rat MAO A (≈450 Å3). An important component of the active site structure of hMAO A is the loop conformation of residues 210-216, which differs from that of hMAO B and rat MAO A. The origin of this structural alteration is suggested to result from long-range interactions in the monomeric form of the enzyme. In addition to serving as a basis for the development of hMAO A specific inhibitors, these data support the proposal that hMAO A involves a change from the dimeric to the monomeric form through a Glu-151 → Lys mutation that is specific of hMAO A [Andrès, A. M., Soldevila, M., Navarro, A., Kidd, K. K., Oliva, B. & Bertranpetit, J. (2004) Hum. Genet. 115, 377-386]. These considerations put into question the use of MAO A from nonhuman sources in drug development for use in humans.
KW - Antidepressant target
KW - Flavin
KW - Membrane protein
KW - Neurotransmitter
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U2 - 10.1073/pnas.0505975102
DO - 10.1073/pnas.0505975102
M3 - Article
C2 - 16129825
AN - SCOPUS:24644437716
SN - 0027-8424
VL - 102
SP - 12684
EP - 12689
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 36
ER -