| Autor: |
Klaus, Maja, Rossini, Emanuele, Linden, Andreas, Paithankar, Karthik S., Zeug, Matthias, Ignatova, Zoya, Urlaub, Henning, Khosla, Chaitan, Köfinger, Jürgen, Hummer, Gerhard, Grininger, Martin |
| Zdroj: |
JACS Au; December 2021, Vol. 1 Issue: 12 p2162-2171, 10p |
| Abstrakt: |
Polyketide synthases (PKSs) are versatile C–C bond-forming enzymes that are broadly distributed in bacteria and fungi. The polyketide compound family includes many clinically useful drugs such as the antibiotic erythromycin, the antineoplastic epothilone, and the cholesterol-lowering lovastatin. Harnessing PKSs for custom compound synthesis remains an open challenge, largely because of the lack of knowledge about key structural properties. Particularly, the domains─well characterized on their own─are poorly understood in their arrangement, conformational dynamics, and interplay in the intricate quaternary structure of modular PKSs. Here, we characterize module 2 from the 6-deoxyerythronolide B synthase by small-angle X-ray scattering and cross-linking mass spectrometry with coarse-grained structural modeling. The results of this hybrid approach shed light on the solution structure of a cis-AT type PKS module as well as its inherent conformational dynamics. Supported by a directed evolution approach, we also find that acyl carrier protein (ACP)-mediated substrate shuttling appears to be steered by a nonspecific electrostatic interaction network. |
| Databáze: |
Supplemental Index |
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