PMID- 38049653
OWN - NLM
STAT- MEDLINE
DCOM- 20240214
LR  - 20240226
IS  - 1755-4349 (Electronic)
IS  - 1755-4330 (Linking)
VI  - 16
IP  - 2
DP  - 2024 Feb
TI  - Subdomain dynamics enable chemical chain reactions in non-ribosomal peptide 
      synthetases.
PG  - 259-268
LID - 10.1038/s41557-023-01361-4 [doi]
AB  - Many peptide-derived natural products are produced by non-ribosomal peptide 
      synthetases (NRPSs) in an assembly-line fashion. Each amino acid is coupled to a 
      designated peptidyl carrier protein (PCP) through two distinct reactions 
      catalysed sequentially by the single active site of the adenylation domain 
      (A-domain). Accumulating evidence suggests that large-amplitude structural 
      changes occur in different NRPS states; yet how these molecular machines 
      orchestrate such biochemical sequences has remained elusive. Here, using 
      single-molecule Forster resonance energy transfer, we show that the A-domain of 
      gramicidin S synthetase I adopts structurally extended and functionally 
      obligatory conformations for alternating between adenylation and 
      thioester-formation structures during enzymatic cycles. Complementary 
      biochemical, computational and small-angle X-ray scattering studies reveal 
      interconversion among these three conformations as intrinsic and hierarchical 
      where intra-A-domain organizations propagate to remodel inter-A-PCP didomain 
      configurations during catalysis. The tight kinetic coupling between structural 
      transitions and enzymatic transformations is quantified, and how the gramicidin S 
      synthetase I A-domain utilizes its inherent conformational dynamics to drive 
      directional biosynthesis with a flexibly linked PCP domain is revealed.
CI  - (c) 2023. The Author(s), under exclusive licence to Springer Nature Limited.
FAU - Sun, Xun
AU  - Sun X
AUID- ORCID: 0000-0002-8079-5530
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
AD  - Department of Integrative Structural and Computational Biology, The Scripps 
      Research Institute, La Jolla, CA, USA.
FAU - Alfermann, Jonas
AU  - Alfermann J
AD  - Institute of Biochemistry, University of Munster, Munster, Germany.
FAU - Li, Hao
AU  - Li H
AUID- ORCID: 0000-0003-2886-5658
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
FAU - Watkins, Maxwell B
AU  - Watkins MB
AUID- ORCID: 0000-0003-4559-2049
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
AD  - Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 
      USA.
FAU - Chen, Yi-Tsao
AU  - Chen YT
AUID- ORCID: 0000-0002-9891-5799
AD  - Institute of Bioinformatics and Systems Biology; Institute of Molecular Medicine 
      and Bioengineering; Department of Biological Science and Technology; Centre for 
      Intelligent Drug Systems and Smart Bio-devices (IDS(2)B), National Yang Ming Chiao 
      Tung University, Hsinchu, Taiwan.
FAU - Morrell, Thomas E
AU  - Morrell TE
AUID- ORCID: 0000-0001-9266-5146
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
FAU - Mayerthaler, Florian
AU  - Mayerthaler F
AUID- ORCID: 0000-0002-8583-7218
AD  - Institute of Biochemistry, University of Munster, Munster, Germany.
FAU - Wang, Chia-Ying
AU  - Wang CY
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
FAU - Komatsuzaki, Tamiki
AU  - Komatsuzaki T
AUID- ORCID: 0000-0001-7175-8474
AD  - Research Centre of Mathematics for Social Creativity, Research Institute for 
      Electronic Science; The Institute for Chemical Reaction Design and Discovery 
      (WPI-ICReDD), Hokkaido University, Sapporo, Japan.
AD  - The Institute of Scientific and Industrial Research, Osaka University, Ibaraki, 
      Japan.
FAU - Chu, Jhih-Wei
AU  - Chu JW
AUID- ORCID: 0000-0003-3842-2893
AD  - Institute of Bioinformatics and Systems Biology; Institute of Molecular Medicine 
      and Bioengineering; Department of Biological Science and Technology; Centre for 
      Intelligent Drug Systems and Smart Bio-devices (IDS(2)B), National Yang Ming Chiao 
      Tung University, Hsinchu, Taiwan.
FAU - Ando, Nozomi
AU  - Ando N
AUID- ORCID: 0000-0001-7062-1644
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA.
AD  - Department of Chemistry and Chemical Biology, Cornell University, Ithaca, NY, 
      USA.
FAU - Mootz, Henning D
AU  - Mootz HD
AUID- ORCID: 0000-0002-3385-0234
AD  - Institute of Biochemistry, University of Munster, Munster, Germany. 
      henning.mootz@uni-muenster.de.
FAU - Yang, Haw
AU  - Yang H
AUID- ORCID: 0000-0003-0268-6352
AD  - Department of Chemistry, Princeton University, Princeton, NJ, USA. 
      hawyang@princeton.edu.
LA  - eng
GR  - No. RGP0031/2010-C202/Human Frontier Science Program (HFSP)/
GR  - GM124847/U.S. Department of Health & Human Services | NIH | National Institute of 
      General Medical Sciences (NIGMS)/
GR  - DFG MO1073/8-1/Deutsche Forschungsgemeinschaft (German Research Foundation)/
PT  - Journal Article
DEP - 20231204
PL  - England
TA  - Nat Chem
JT  - Nature chemistry
JID - 101499734
RN  - EC 6.3.2.- (non-ribosomal peptide synthase)
RN  - 1405-97-6 (Gramicidin)
RN  - EC 6.3.2.- (Peptide Synthases)
SB  - IM
MH  - Protein Structure, Tertiary
MH  - *Gramicidin
MH  - *Peptide Synthases/chemistry
MH  - Catalytic Domain
EDAT- 2023/12/05 00:42
MHDA- 2024/02/09 00:42
CRDT- 2023/12/04 23:40
PHST- 2022/06/06 00:00 [received]
PHST- 2023/10/03 00:00 [accepted]
PHST- 2024/02/09 00:42 [medline]
PHST- 2023/12/05 00:42 [pubmed]
PHST- 2023/12/04 23:40 [entrez]
AID - 10.1038/s41557-023-01361-4 [pii]
AID - 10.1038/s41557-023-01361-4 [doi]
PST - ppublish
SO  - Nat Chem. 2024 Feb;16(2):259-268. doi: 10.1038/s41557-023-01361-4. Epub 2023 Dec 
      4.