2z5y
From Proteopedia
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'''Crystal Structure of Human Monoamine Oxidase A (G110A) with Harmine''' | '''Crystal Structure of Human Monoamine Oxidase A (G110A) with Harmine''' | ||
| + | |||
| + | ==Overview== | ||
| + | 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. | ||
==About this Structure== | ==About this Structure== | ||
2Z5Y is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Z5Y OCA]. | 2Z5Y is a [[Single protein]] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Z5Y OCA]. | ||
| - | + | ||
| + | ==Reference== | ||
| + | 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:[http://www.ncbi.nlm.nih.gov/pubmed/18391214 18391214] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
[[Category: Ma, J.]] | [[Category: Ma, J.]] | ||
| - | [[Category: Son, S.]] | + | [[Category: Son, S Y.]] |
[[Category: Tsukihara, T.]] | [[Category: Tsukihara, T.]] | ||
[[Category: Yoshimura, M.]] | [[Category: Yoshimura, M.]] | ||
| - | [[Category: | + | [[Category: Acetylation]] |
| - | [[Category: | + | [[Category: Catecholamine metabolism]] |
| - | [[Category: | + | [[Category: Dimethyldecylphosphine oxide]] |
| - | [[Category: | + | [[Category: Fad]] |
| - | [[Category: | + | [[Category: Flavoprotein]] |
| - | [[Category: | + | [[Category: G110a]] |
| - | [[Category: | + | [[Category: Harmine]] |
| - | [[Category: | + | [[Category: Human monoamine oxidase some]] |
| - | [[Category: | + | [[Category: Mitochondrion]] |
| - | [[Category: | + | [[Category: Mutant]] |
| - | [[Category: | + | [[Category: Neurotransmitter degradation]] |
| - | [[Category: | + | [[Category: Oxidoreductase]] |
| - | [[Category: | + | [[Category: Polymorphism]] |
| - | [[Category: | + | [[Category: Single helix trans-membrane protein]] |
| - | [[Category: | + | [[Category: Transmembrane]] |
| - | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Apr 24 09:31:33 2008'' | |
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | |
Revision as of 06:31, 24 April 2008
Crystal Structure of Human Monoamine Oxidase A (G110A) with Harmine
Overview
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.
About this Structure
2Z5Y is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
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 Page seeded by OCA on Thu Apr 24 09:31:33 2008
Categories: Homo sapiens | Single protein | Ma, J. | Son, S Y. | Tsukihara, T. | Yoshimura, M. | Acetylation | Catecholamine metabolism | Dimethyldecylphosphine oxide | Fad | Flavoprotein | G110a | Harmine | Human monoamine oxidase some | Mitochondrion | Mutant | Neurotransmitter degradation | Oxidoreductase | Polymorphism | Single helix trans-membrane protein | Transmembrane
