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PDBsum entry 6bbs
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Lyase/lyase inhibitor
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PDB id
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6bbs
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References listed in PDB file
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Key reference
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Title
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&Quot;to be or not to be" protonated: atomic details of human carbonic anhydrase-Clinical drug complexes by neutron crystallography and simulation.
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Authors
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A.Kovalevsky,
M.Aggarwal,
H.Velazquez,
M.J.Cuneo,
M.P.Blakeley,
K.L.Weiss,
J.C.Smith,
S.Z.Fisher,
R.Mckenna.
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Ref.
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Structure, 2018,
26,
383.
[DOI no: ]
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PubMed id
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Abstract
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Human carbonic anhydrases (hCAs) play various roles in cells, and have been drug
targets for decades. Sequence similarities of hCA isoforms necessitate designing
specific inhibitors, which requires detailed structural information for
hCA-inhibitor complexes. We present room temperature neutron structures of hCA
II in complex with three clinical drugs that provide in-depth analysis of drug
binding, including protonation states of the inhibitors, hydration water
structure, and direct visualization of hydrogen-bonding networks in the enzyme's
active site. All sulfonamide inhibitors studied bind to the Zn metal center in
the deprotonated, anionic, form. Other chemical groups of the drugs can remain
neutral or be protonated when bound to hCA II. MD simulations have shown that
flexible functional groups of the inhibitors may alter their conformations at
room temperature and occupy different sub-sites. This study offers insights into
the design of specific drugs to target cancer-related hCA isoform IX.
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Secondary reference #1
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Title
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Generalized X-Ray and neutron crystallographic analysis: more accurate and complete structures for biological macromolecules.
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Authors
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P.D.Adams,
M.Mustyakimov,
P.V.Afonine,
P.Langan.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2009,
65,
567-573.
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PubMed id
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