% IMPORTANT: The following is UTF-8 encoded.  This means that in the presence
% of non-ASCII characters, it will not work with BibTeX 0.99 or older.
% Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or
% “biber”.

@ARTICLE{Sevenich:908819,
      author       = {Sevenich, Marc and van den Heuvel, Joop and Gering, Ian and
                      Mohrlüder, Jeannine and Willbold, Dieter},
      title        = {{A} {S}o-{F}ar {O}verlooked {S}econdary {C}onformation
                      {S}tate in the {B}inding {M}ode of {SARS}-{C}o{V}-2 {S}pike
                      {P}rotein to {H}uman {ACE}2 and {I}ts {C}onversion {R}ate
                      {A}re {C}rucial for {E}stimating {I}nfectivity {E}fficacy of
                      the {U}nderlying {V}irus {V}ariant},
      journal      = {Journal of virology},
      volume       = {96},
      number       = {13},
      issn         = {0022-538X},
      address      = {Baltimore, Md.},
      publisher    = {Soc.},
      reportid     = {FZJ-2022-02856},
      pages        = {e00685-22},
      year         = {2022},
      abstract     = {Since its outbreak in 2019, severe acute respiratory
                      syndrome coronavirus 2 (SARS-CoV-2) has spread with high
                      transmission efficiency across the world, putting health
                      care as well as economic systems under pressure. During the
                      course of the pandemic, the originally identified SARS-CoV-2
                      variant has been multiple times replaced by various mutant
                      versions, which showed enhanced fitness due to increased
                      infection and transmission rates. In order to find an
                      explanation for why SARS-CoV-2 and its emerging mutated
                      versions showed enhanced transmission efficiency compared
                      with SARS-CoV (2002), an enhanced binding affinity of the
                      spike protein to human angiotensin converting enzyme 2
                      (hACE2) has been proposed by crystal structure analysis and
                      was identified in cell culture models. Kinetic analysis of
                      the interaction of various spike protein constructs with
                      hACE2 was considered to be best described by a
                      Langmuir-based 1:1 stoichiometric interaction. However, we
                      demonstrate in this report that the SARS-CoV-2 spike protein
                      interaction with hACE2 is best described by a two-step
                      interaction, which is defined by an initial binding event
                      followed by a slower secondary rate transition that enhances
                      the stability of the complex by a factor of ~190 (primary
                      versus secondary state) with an overall equilibrium
                      dissociation constant (KD) of 0.20 nM. In addition, we
                      show that the secondary rate transition is not only present
                      in SARS-CoV-2 wild type (“wt”; Wuhan strain) but also
                      found in the B.1.1.7 variant, where its transition rate is
                      5-fold increased.IMPORTANCE The current SARS-CoV-2 pandemic
                      is characterized by the high infectivity of SARS-CoV-2 and
                      its derived variants of concern (VOCs). It has been widely
                      assumed that the reason for its increased cell entry
                      compared with SARS-CoV (2002) is due to alterations in the
                      viral spike protein, where single amino acid residue
                      substitutions can increase affinity for hACE2. So far, the
                      interaction of a single unit of the CoV-2 spike protein has
                      been described using the 1:1 Langmuir interaction kinetic.
                      However, we demonstrate here that there is a secondary state
                      binding step that may be essential for novel VOCs in order
                      to further increase their infectivity. These findings are
                      important for quantitatively understanding the infection
                      process of SARS-CoV-2 and characterization of emerging
                      SARS-CoV-2 variants of spike proteins. Thus, they provide a
                      tool for predicting the potential infectivity of the
                      respective viral variants based on secondary rate transition
                      and secondary complex stability.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {35674432},
      UT           = {WOS:000810989000003},
      doi          = {10.1128/jvi.00685-22},
      url          = {https://juser.fz-juelich.de/record/908819},
}