PSI Structural Biology Knowledgebase

PSI | Structural Biology Knowledgebase
Header Icons

Related Articles
Families in Gene Neighborhoods
June 2015
Signaling: A Platform for Opposing Functions
May 2015
Nuclear Pore Complex: A Flexible Transporter
February 2015
Nuclear Pore Complex: Higher Resolution of Macromolecules
February 2015
Nuclear Pore Complex: Integrative Approach to Probe Nup133
February 2015
Piecing Together the Nuclear Pore Complex
February 2015
iTRAQing the Ubiquitinome
July 2014
CAAX Endoproteases
August 2013
The Immune System: A Strong Competitor
June 2013
The Immune System: Strand Swapping for T-Cell Inhibition
June 2013
PDZ Domains
April 2013
Protein Interaction Networks: Adding Structure to Protein Networks
April 2013
Protein Interaction Networks: Morph to Assemble
April 2013
Protein Interaction Networks: Reading Between the Lines
April 2013
Protein Interaction Networks: When the Sum Is Greater than the Parts
April 2013
Alpha-Catenin Connections
March 2013
Cytochrome Oxidase
November 2012
Bacterial Phosphotransferase System
October 2012
Solute Channels
September 2012
Budding ensemble
August 2012
The machines behind the spindle assembly checkpoint
June 2012
G Protein-Coupled Receptors
May 2012
Revealing the Nuclear Pore Complex
March 2012
Topping off the proteasome
March 2012
Anchoring's the way
February 2012
Reading out regioselectivity
December 2011
An effective and cooperative dimer
November 2011
PDZ domains: sometimes it takes two
November 2011
Raising a glass to GLIC
August 2011
A2A Adenosine Receptor
May 2011
A growing family
February 2011
FERM-ly bound
February 2011
January 2011
Guard cells pick up the SLAC
December 2010
Zinc Transporter ZntB
July 2010
Zinc Transporter ZntB
July 2010
Importance of extension for integrin
June 2010
Spot protein-protein interactions… fast
March 2010
Alg13 Subunit of N-Acetylglucosamine Transferase
February 2010
Urea transporter
February 2010
Two-component signaling
December 2009
ABA receptor...this time for real?
November 2009
Network coverage
November 2009
Get3 into the groove
October 2009
Guanine Nucleotide Exchange Factor Vav1 and Rho GTPase Rac1
October 2009
GPCR subunits: Separate but not equal
September 2009
Proofreading RNA
July 2009
Ribonuclease and Ribonuclease Inhibitor
April 2009
The elusive helicase
April 2009
Click for cancer-protein interactions
December 2008

Research Themes Protein-protein interactions

Cytochrome Oxidase

SBKB [doi:10.3942/psi_sgkb/fm_2012_11]
Featured System - November 2012
Short description: Cytochrome oxidase is the foundation of aerobic respiration.

Cytochrome oxidase is the foundation of aerobic respiration. Our cells rip apart molecules of food, using the favorable energetics of the process to produce ATP. At the end of the process, however, the pieces need to be discarded. In particular, the electron transport chain saps the energy out of the electrons that are extracted from food molecules, and the cell needs a way to get rid of them. This is the job of cytochrome oxidase--it loads these electrons onto oxygen, creating water. In the process, it also pumps protons across a membrane, helping to create the electrochemical gradient that fuels ATP production.

Tools of the Trade

Cytochrome oxidase performs a tricky job: oxygen molecules are small and difficult to hold in one place. This job requires specialized chemical tools to make sure that everything goes as planned, which is particularly important for this reaction, since destructive intermediates may be formed if the process stops part way through. The active site of cytochrome oxidase relies on several unusual cofactors: two heme groups and a copper ion that grip the oxygen molecule, as well as an unusual pair of copper ions that guide the electrons to the reaction site.

Variations on a Theme

Looking at cytochrome oxidase from many organisms, we find commonalities and differences. The one shown here on the left is from mitochondria (PDB entry 1v54). It has the prototypical structure, with three core subunits, termed I, II and III, that perform the reaction, surrounded by a host of smaller subunits that tune its action. PSI researchers have recently solved the structure of an unusual variation on this theme, shown on the right (PDB entry 2yev). This cytochrome oxidase is made by the bacterium Thermus thermophilus. In it, the I and III subunits are fused into one long chain, and surprisingly, cytochrome c is fused to the II subunit. In most cases, cytochrome c is a separate, soluble protein that delivers electrons to cytochrome oxidase. In this bacterium, however, the cytochrome is fixed in place.

Proton Pumping

There are more surprises in this structure as we look closer into the internal mechanisms. The coordinated action of creating water from oxygen and pumping protons requires two sources of protons: one for the reaction and one for the pumping. These are delivered via two separate pathways in the enzyme. Previous structures have identified a key glutamate amino acid that acts as the gate, controlling the flow of protons along one pathway of amino acids and water molecules that runs through the enzyme. The new structure, however, is missing this glutamate, and the gating is instead thought to be performed by a duo of tyrosine and serine. To take a closer look at these two proton pathways, the JSmol tab below displays an interactive JSmol.

Proton Channels in Cytochrome Oxidase (PDB entries 2yev and 3hb3)

The two proton pathways are shown in green (D-pathway) and yellow (K-pathway). Water molecules are shown in large spheres. The key gating amino acids are seen at the top of the green pathway. The active site also includes the heme cofactors (pink spheres), the copper ion (turquoise sphere), two water molecules in the site where oxygen binds (bright red spheres), and an unusual histidine and tyrosine that are crosslinked together (red ball-and-stick). Use the button to switch between the Therm


  1. Lyons, J. A. et al. Structural insights into electron transfer in caa3-type cytochrome oxidase. Nature 487, 514-518 (2012).

  2. Pereira, M. M., Sousa, F. L., Verissimo, A. F. & Teixeira, M. Looking for the minimum common denominator in haem-copper oxygen reductases: towards a unified catalytic mechanism. Biochim. Biophys. Acta 1777, 929-934 (2008).

  3. Ferguson-Miller, S. & Babcock, G. T. Heme/copper terminal oxidases. Chem. Rev. 96, 2889-2907 (1996).

Structural Biology Knowledgebase ISSN: 1758-1338
Funded by a grant from the National Institute of General Medical Sciences of the National Institutes of Health