PDBsum entry 3mhc

Lyase

PDB id

3mhc

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Contents

			Protein chain

					257 a.a. *

			Ligands

					ARZ

			Metals

					_ZN

			Waters ×229

* Residue conservation analysis

PDB id:

3mhc

Links

Name:

Lyase

Title:

Crystal structure of human cabonic anhydrase ii in adduct with an adamantyl analogue of acetazolamide in a novel hydrophobic binding pocket

Structure:

Carbonic anhydrase 2. Chain: a. Synonym: carbonic anhydrase ii, ca-ii, carbonate dehydratase ii, carbonic anhydrasE C, cac. Engineered: yes

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ca2. Expressed in: escherichia coli. Expression_system_taxid: 511693.

Resolution:

1.70Å

R-factor:

0.168

R-free:

0.212

Authors:

B.S.Avvaru

Key ref:

B.S.Avvaru et al. (2010). Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors. Bioorg Med Chem Lett, 20, 4376-4381. PubMed id: 20605094

Date:

07-Apr-10

Release date:

21-Jul-10

PROCHECK

	Headers

	References

Protein chain

P00918 (CAH2_HUMAN) - Carbonic anhydrase 2 from Homo sapiens

Seq: Struc:					260 a.a. 257 a.a.

Key:

PfamA domain

Secondary structure

CATH domain



		Enzyme reactions

Enzyme class:

E.C.4.2.1.1 - carbonic anhydrase.

[IntEnz] [ExPASy] [KEGG] [BRENDA]

Reaction:

hydrogencarbonate + H⁺ = CO2 + H2O

hydrogencarbonate	+	H(+)	=	CO2	+	H2O

Cofactor:

Zn(2+)

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

Added reference

	Bioorg Med Chem Lett 20:4376-4381 (2010)
PubMed id: 20605094

Carbonic anhydrase inhibitors. The X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors.
B.S.Avvaru, J.M.Wagner, A.Maresca, A.Scozzafava, A.H.Robbins, C.T.Supuran, R.McKenna.

ABSTRACT

We investigated the inhibitory activity of several 1,3,4-thiadiazole-sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.

Literature references that cite this PDB file's key reference

PubMed id

Reference

21515057

F.Carta, V.Garaj, A.Maresca, J.Wagner, B.S.Avvaru, A.H.Robbins, A.Scozzafava, R.McKenna, and C.T.Supuran (2011).
Sulfonamides incorporating 1,3,5-triazine moieties selectively and potently inhibit carbonic anhydrase transmembrane isoforms IX, XII and XIV over cytosolic isoforms I and II: Solution and X-ray crystallographic studies.

Bioorg Med Chem, 19, 3105-3119.

PDB codes:

3mmf 3mna

21549597

F.Mincione, F.Benedini, S.Biondi, A.Cecchi, C.Temperini, G.Formicola, I.Pacileo, A.Scozzafava, E.Masini, and C.T.Supuran (2011).
Synthesis and crystallographic analysis of new sulfonamides incorporating NO-donating moieties with potent antiglaucoma action.

Bioorg Med Chem Lett, 21, 3216-3221.

PDB code:

3ni5

21354674

J.Liu, D.Obando, V.Liao, T.Lifa, and R.Codd (2011).
The many faces of the adamantyl group in drug design.

Eur J Med Chem, 46, 1949-1963.

20922253

F.Pacchiano, M.Aggarwal, B.S.Avvaru, A.H.Robbins, A.Scozzafava, R.McKenna, and C.T.Supuran (2010).
Selective hydrophobic pocket binding observed within the carbonic anhydrase II active site accommodate different 4-substituted-ureido-benzenesulfonamides and correlate to inhibitor potency.

Chem Commun (Camb), 46, 8371-8373.

PDB codes:

3mzc 3n0n 3n2p 3n3j 3n4b

The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.