PDE enzymes are composed of 3 functional domains: an N-terminal cyclin fold domain, a linker helical domain and a C-terminal helical bundle domain (see figure 3). The active site is a deep pocket at the junction of the 3 subdomains and is lined with highly conserved residues between isotypes of PDE. The pocket is approximately 15 Å deep and the opening is approximately 20 by 10 Å. The volume of the active site has been calculated to be between 875 and 927 Å. The active site of PDE5 has been described as subdivided into 3 main regions based on its crystal structure in complex with sildenafil: 
*M site: contains both a zinc and magnesium ion. The role of the ions is to stabilize the structure and activation of hydroxide to mediate the reaction. Current PDE5 inhibitors do not interact with the metal ions, in contrast with cGMP. Direct or indirect interactions may improve the potency of future inhibitors.
*Q pocket: it is believed that the guanidine group of cGMP binds in this region as the Q pocket accommodates the pyrazolopyrimidinone group (see figure 4) of sildenafil. The pyrazolopyrimidinone of sildenafil mimics that of the guanine in cGMP and has the same H-bond donor and acceptor features, forming a bidendrate H-bond with Q817. Card et al. describe the Q pocket as subdivided into 3 parts:	
**A saddle formed by the conserved glutamine (Q817 in PDE5A, Q443 in PDE4B and Q369 in PDE4D) and the P clamp (a hydrophobic clamp at the narrow side of the active sites pocket, formed of invariant purine-selective glutamine and a pair of conserved residues).
**2 narrow, hydrophobic pockets, Q1 and Q2, composed mainly of hydrophobic residues flanking the saddle.
*L region: the methyl piperazine group (see figure 4) of sildenafil is surrounded by Tyr 664, Met 816, Ala 823 and Gly 819 residues, and residues 662-664 form a lid over the pocket narrowing the entrance to the active site of PDE5.
Jeon et al. also describe a fourth pocket called the H pocket which is hydrophobic and accommodates the ethoxyphenyl group of sildenafil
The 3 PDE5 inhibitors already on the market, sildenafil, tadalafil and vardenafil, occupy part of the active site, mainly around the Q pocket and sometimes the M pocket as well and all 3 interact with the active site in 3 important manners:
#interaction between the metal ions mediated through water
#hydrogen bonding with the saddle of the Q pocket
#hydrophobic interaction with hydrophobic residues lining the cavity of the active site.
It has also been described that the hydrophobic interaction with the Q1 and Q2 pockets are important for inhibitor potency and differences between isotypes of PDE in the Q2 pocket can be exploited for selectivity between isotypes.