*This website was produced as an assignment for an undergraduate course at Davidson College.*

3D Structure of Serotonin N-Acetyltransferase before and after interaction with AcCoA

CPK Color Scheme

On this page, you can see the 3D structure of the serotonin N-acetyltransferase molecule. On the left frame you can see the unbound macromolecule whereas in the right frame you see the macromolecule bound to potent bisubstrate analog inhibitor, which represents the Acetyl Coenzyme A (AcCoA). Serotonin N-Acetyltransferase (AANAT) is the rate determining factor of the metabolic path for the production of melatonin, the levels of which allow animals to adapt to cycles of nigh and day. Specifically AANAT catalyzes the acetylation of serotonin, using AcCoA's acetyl group. For more detailed information on the structure and function of AANAT click here.

Reset and spin the serotonin N-acetyltransferase molecules.

Highlight the catalytic core (green) of the protein which contains both serotonin's binding site and AcCoA's binding site. The blue traces in the amino and carboxyl termini of the protein make up regulatory regions, which include PKA phosphorylation sites. On the right frame notice the AcCoA molecule (yellow).

Here look at AcCoA molecule in the right frame. In vertebrates, the binding of AcCoA does not only ensure supply of an acetyl group to the complex but as I shall explain later promotes a conformational change of AANAT that also enables the binding of serotonin.

Highlight the AANAT's secondary structure. AANAT is made up of eight b sheets, (red) and five a helices (green).In both bound and unbound confirmations, the a helices encircle the b sheets and the b sheets form a V-shaped cleft. The point of convergence of that V-shape confirmation (zoomed in area) is where the AcCoA binds, which is why in the bound complex the b sheets appear disrupted.

Look at the catalytic loops created by the secondary structures mentioned above. These three loops create a pocket in which both substrates (Serotonin and AcCoA) are going to bind. On the left frame because of the lack of an AcCoA, however, Loop 1 is blocking the active site of the protein but on the right frame the binding of AcCoA has led to a conformational change that has uncovered the active site. Notice also that in left frame, the helix preceding loop 1 has now been extended and has become part of the loop itself. Finally, notice the salt bridge that is created by the interaction of a glutamic acid and argenine keeps Loop 1 stable in this confirmation and it's not seen in uncomplexed protein.

Highlight the hydrophobic residues that exist in the active site. The funnel-like active site of AANAT, created by the three loops, is predominantly hydrophobic, as seen in both frames. However after the conformational change (right frame) the hydrophobic residues aggregate very closely which shows that only small molecules (like serotonin) could enter AANAT's active site.

Highlight the Histidine 120, 122 and Tyrosine 168 catalytic residues. All three of these amino acids play a very important role in the catalytic properties of AANAT. On the one hand the histidine residues initiate the transfer of the acetyl group from AcCoA to the serotonin and on the other hand the tyrosine residue is involved in the expulsion of the deacetylated AcCoA molecule.


Coon SL, Klein DC. Evolution of arylalkylamine N-acetyltransferase: Emergence and divergence. Molecular and Cellular Endocrinology 2006; 252: 2-10. Article.

Hickman AB, Klein DA, Dyda F. Melatonin Biosynthesis: The Structure of Serotonin N-Acetyltransferase at 2.5A° Resolution Suggests a Catalytic Mechanism. Molecular Cell 1999; 3: 23-32. PubMed and PDB.

Klein DC. Arylalkylamine N-Acetyltransferase: "the Timezyme". The Journal of Biological Chemistry 2006; 282: 4233-4237. Article.

Scheibner KA, De Angelis J, Burley SK, Cole PA. Investigation of the Roles of Catalytic Residues in Serotonin N-Acetyltransferase. The Journal of Biological Chemistry 2002; 277: 18118-18126. Article.

Wolf E,   De Angelis J,   Khalil EM,   Cole PA,   Burley, SK. X-ray crystallographic studies of serotonin N-acetyltransferase catalysis and inhibition.Journal of Molecular Biology 2002; 317: 215-24. PubMed and PDB.


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