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The substrates, CO and CO\n                    <jats:sub>2<\/jats:sub>\n                    , need therefore to be transported through the protein matrix to reach the active site. The most likely pathway for intra\u2010protein diffusion is the hydrophobic channel identified in the crystal structures. We used site\u2010directed mutagenesis in an extensive manner to study the role of the highly conserved isoleucine 563 of\n                    <jats:italic>Thermococcus sp<\/jats:italic>\n                    . AM4 CODH2. Certain substitutions significantly change the biochemical properties of the enzyme (K\n                    <jats:sub>M<\/jats:sub>\n                    for CO, catalytic efficiency, product inhibition constant, catalytic bias, \u2026), and increase its resistance to the inhibitor O\n                    <jats:sub>2<\/jats:sub>\n                    , showing that isoleucine 563 plays a key role in determining access to the active site. The mutations have the same effects on the rates of binding of CO and O\n                    <jats:sub>2<\/jats:sub>\n                    , showing that the two molecules follow the same pathway and are not discriminated by the protein matrix. The I563F mutation decreases the bimolecular rate constant of inhibition by O\n                    <jats:sub>2<\/jats:sub>\n                    15\u2010fold and increases the IC50 20\u2010fold. This is the strongest improvement in O\n                    <jats:sub>2<\/jats:sub>\n                    resistance reported so far, but it comes at the cost of reduced substrate affinity.\n                  <\/jats:p>","DOI":"10.1002\/anie.6262238","type":"journal-article","created":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T03:42:13Z","timestamp":1789184533000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A Conserved Isoleucine Gates the Diffusion of CO and O\n                    <sub>2<\/sub>\n                    to the Active Site of NiFe CO\u2010Dehydrogenase"],"prefix":"10.1002","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5099-1066","authenticated-orcid":false,"given":"Laura","family":"Opdam","sequence":"first","affiliation":[{"name":"Aix\u2010Marseille Universit\u00e9, CNRS, BIP  Marseille 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