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|2z5x, resolution 2.20Å ()|
|Ligands:||, , ,|
Crystal Structure of Human Monoamine Oxidase A with Harmine
The mitochondrial outer membrane-anchored monoamine oxidase (MAO) is a biochemically important flavoenzyme that catalyzes the deamination of biogenic and xenobiotic amines. Its two subtypes, MAOA and MAOB, are linked to several psychiatric disorders and therefore are interesting targets for drug design. To understand the relationship between structure and function of this enzyme, we extended our previous low-resolution rat MAOA structure to the high-resolution wild-type and G110A mutant human MAOA structures at 2.2 and 2.17 A, respectively. The high-resolution MAOA structures are similar to those of rat MAOA and human MAOB, but different from the known structure of human MAOA [De Colibus L, et al. (2005) Proc Natl Acad Sci USA 102:12684-12689], specifically regarding residues 108-118 and 210-216, which surround the substrate/inhibitor cavity. The results confirm that the inhibitor selectivity of MAOA and MAOB is caused by the structural differences arising from Ile-335 in MAOA vs. Tyr-326 in MAOB. The structures exhibit a C-terminal transmembrane helix with clear electron density, as is also seen in rat MAOA. Mutations on one residue of loop 108-118, G110, which is far from the active center but close to the membrane surface, cause the solubilized enzyme to undergo a dramatic drop in activity, but have less effect when the enzyme is anchored in the membrane. These results suggest that the flexibility of loop 108-118, facilitated by anchoring the enzyme into the membrane, is essential for controlling substrate access to the active site. We report on the observation of the structure-function relationship between a transmembrane helical anchor and an extra-membrane domain.
Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors., Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T, Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5739-44. Epub 2008 Apr 7. PMID:18391214
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
[AOFA_HUMAN] Defects in MAOA are the cause of Brunner syndrome (BRUNS) [MIM:300615]. Brunner syndrome is a form of X-linked non-dysmorphic mild mental retardation. Male patients are affected by a syndrome of borderline mental retardation and exhibit abnormal behavior, including disturbed regulation of impulsive aggression. Obligate female carriers have normal intelligence and behavior.
[AOFA_HUMAN] Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral tissues. MAOA preferentially oxidizes biogenic amines such as 5-hydroxytryptamine (5-HT), norepinephrine and epinephrine.
About this Structure
- Son SY, Ma J, Kondou Y, Yoshimura M, Yamashita E, Tsukihara T. Structure of human monoamine oxidase A at 2.2-A resolution: the control of opening the entry for substrates/inhibitors. Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5739-44. Epub 2008 Apr 7. PMID:18391214