Journal
NUCLEIC ACIDS RESEARCH
Volume 44, Issue 1, Pages 63-74Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1091
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Funding
- National Institutes of Health Ruth L. Kirschstein National Research Service Award [F31-GM101946]
- Chemical Biology Training Program Fellowship [T32-GM092714]
- National Science Foundation Louis Stokes Alliance for Minority Participation [HRD-0929353]
- Alliance for Graduate Education and the Professoriate-Transformation Fellowship [HRD-1311318]
- National Institutes of Health Biology Partnership in Research and Education Program [R25-GM050070]
- National Institutes of Health (NIH)
- National Institute of General Medical Sciences (NIGMS) [R01-GM090205]
- National Instititues of Health (NIH) [R01-GM100021]
- NSF Petascale Computational Resource (PRAC) Award from the National Science Foundation [OCI-1036208]
- National Science Foundation [HRD-1311318]
- Direct For Education and Human Resources
- Division Of Human Resource Development [1311318] Funding Source: National Science Foundation
- Office of Advanced Cyberinfrastructure (OAC)
- Direct For Computer & Info Scie & Enginr [1515572] Funding Source: National Science Foundation
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Transcription factors (TF) can change shape to bind and recognize DNA, shifting the energy landscape from a weak binding, rapid search mode to a higher affinity recognition mode. However, the mechanism(s) driving this conformational change remains unresolved and in most cases high-resolution structures of the non-specific complexes are unavailable. Here, we investigate the conformational switch of the human mitochondrial transcription termination factor MTERF1, which has a modular, superhelical topology complementary to DNA. Our goal was to characterize the details of the non-specific search mode to complement the crystal structure of the specific binding complex, providing a basis for understanding the recognition mechanism. In the specific complex, MTERF1 binds a significantly distorted and unwound DNA structure, exhibiting a protein conformation incompatible with binding to B-form DNA. In contrast, our simulations of apo MTERF1 revealed significant flexibility, sampling structures with superhelical pitch and radius complementary to the major groove of B-DNA. Docking these structures to B-DNA followed by unrestrained MD simulations led to a stable complex in which MTERF1 was observed to undergo spontaneous diffusion on the DNA. Overall, the data support an MTERF1-DNA binding and recognition mechanism driven by intrinsic dynamics of the MTERF1 superhelical topology.
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