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3n3g

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4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important

Structural highlights

3n3g is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.6Å
Ligands:	, , , , ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

CATS_HUMAN Thiol protease. Key protease responsible for the removal of the invariant chain from MHC class II molecules. The bond-specificity of this proteinase is in part similar to the specificities of cathepsin L and cathepsin N.

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

Publication Abstract from PubMed

Using computer aided modelling studies, a new extended P2/S2 interaction was identified. This extended region can accommodate a variety of functional groups, such as aryls and basic amines. It was discovered that the N3 nitrogen of the pyrimidine-2-carbonitrile is critical for its cathepsin cysteine protease inhibition. N1 nitrogen also contributes to the inhibitory activity, but to a very limited degree. An 'in situ double activation' mechanism was proposed to explain these results.

4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important.,Cai J, Fradera X, van Zeeland M, Dempster M, Cameron KS, Bennett DJ, Robinson J, Popplestone L, Baugh M, Westwood P, Bruin J, Hamilton W, Kinghorn E, Long C, Uitdehaag JC Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10. Epub 2010 Jun 10. PMID:20580231^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Cai J, Fradera X, van Zeeland M, Dempster M, Cameron KS, Bennett DJ, Robinson J, Popplestone L, Baugh M, Westwood P, Bruin J, Hamilton W, Kinghorn E, Long C, Uitdehaag JC. 4-(3-Trifluoromethylphenyl)-pyrimidine-2-carbonitrile as cathepsin S inhibitors: N3, not N1 is critically important. Bioorg Med Chem Lett. 2010 Aug 1;20(15):4507-10. Epub 2010 Jun 10. PMID:20580231 doi:10.1016/j.bmcl.2010.06.043