5A6H

Synthesis, carbonic anhydrase inhibition and protein X-ray structure of the unusual natural product primary sulfonamide Psammaplin C

Summary for 5A6H

• Entry DOI: 10.2210/pdb5a6h/pdb
• Descriptor: CARBONIC ANHYDRASE 2, ZINC ION, DIMETHYL SULFOXIDE, ... (5 entities in total)
• Functional Keywords: lyase, carbonic anhydrase inhibitor, natural product
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 30573.25

Authors

Mujumdar, P.,Supuran, C.T.,Peat, T.S.,Poulsen, S. (deposition date: 2015-06-26, release date: 2016-05-25, Last modification date: 2024-01-10)

Primary citation

Mujumdar, P.,Teruya, K.,Tonissen, K.F.,Vullo, D.,Supuran, C.T.,Peat, T.S.,Poulsen, S.
An Unusual Natural Product Primary Sulfonamide: Synthesis, Carbonic Anhydrase Inhibition and Protein X-Ray Structures of Psammaplin C.
J.Med.Chem., 59:5462-, 2016

PubMed Abstract: Psammaplin C is one of only two described natural product primary sulfonamides. Here we report the synthesis of psammaplin C and evaluate the inhibition profile against therapeutically relevant carbonic anhydrase (CA) zinc metalloenzymes. The compound exhibited unprecedented inhibition of an important cancer-associated isozyme, hCA XII, with a Ki of 0.79 nM. The compound also displayed good isoform selectivity for hCA XII over other CAs. We present the first reported protein X-ray crystal structures of psammaplin C in complex with human CAs. We engineered the easily crystallized hCA II enzyme to mimic both the hCA IX and hCA XII binding sites and then utilized protein X-ray crystallography to determine the binding pose of psammaplin C within the hCA II, hCA IX, and hCA XII mimic active sites, all to high resolution. This is the first time a natural product primary sulfonamide inhibitor has been assessed for inhibition and binding to CAs.

PubMed: 27172398
DOI: 10.1021/ACS.JMEDCHEM.6B00443

Experimental method

X-RAY DIFFRACTION (1.57 Å)