3EFI

Carbonic anhydrase activators: Kinetic and X-ray crystallographic study for the interaction of d- and l-tryptophan with the mammalian isoforms I-XIV

Summary for 3EFI

• Entry DOI: 10.2210/pdb3efi/pdb
• Descriptor: Carbonic anhydrase 2, ZINC ION, MERCURIBENZOIC ACID, ... (5 entities in total)
• Functional Keywords: carbonic anhydrase, activators, aminoacids, oxo-acid, acetylation, cytoplasm, disease mutation, lyase, metal-binding, polymorphism, zinc
• Cellular location: Cytoplasm : P00918
• Total number of polymer chains: 1
• Total formula weight: 29880.40

Authors

Temperini, C.,Innocenti, A.,Scozzafava, A.,Supuran, C.T. (deposition date: 2008-09-09, release date: 2008-09-30, Last modification date: 2023-11-01)

Primary citation

Temperini, C.,Innocenti, A.,Scozzafava, A.,Supuran, C.T.
Carbonic anhydrase activators: kinetic and X-ray crystallographic study for the interaction of D- and L-tryptophan with the mammalian isoforms I-XIV
Bioorg.Med.Chem., 16:8373-8378, 2008

PubMed Abstract: An activation study of mammalian carbonic anhydrase (CA, EC 4.2.1.1) isoforms I-XIV with D- and L-tryptophan has been performed both by means of kinetic and X-ray crystallographic techniques. These compounds show a time dependent activity against isozyme CA II, with activation constants of 1.13 microM for L-Trp and 0.37 microM for D-Trp, respectively, after 24 h of incubation between enzyme and activator. The high resolution X-ray crystal structure of the hCA II-D-Trp adduct revealed the activator to bind in a totally unprecedented way to the enzyme active site as compared to histamine, L-/D-Phe, L-/D-His or L-adrenaline. D-Trp is anchored at the edge of the CA II active site entrance, strongly interacting with amino acid residues Asp130, Phe131 and Gly132 as well as with a loop of a second symmetry related protein molecule from the asymmetric unit, by means of hydrogen bonds and several weak van der Waals interactions involving Glu234, Gly235, Glu236 and Glu238. Thus, a second activator binding site (B) within the CA II cavity has been detected, where only D-Trp was shown so far to bind, in addition to the activator binding site A, in which histamine, L-/D-Phe, and L-/D-His are bound. These findings explain the strong affinity of D-Trp for CA II and may be useful for designing novel classes of CA activators by using this compound as lead molecule.

PubMed: 18774300
DOI: 10.1016/j.bmc.2008.08.043

Experimental method

X-RAY DIFFRACTION (1.75 Å)