The BOHR effect before Perutz

Brunori, Maurizio

doi:10.1002/bmb.20629

Cited by 5 publications

(6 citation statements)

References 18 publications

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“…As mentioned earlier, a number of the His p K a ’s were not accessible to NMR in the measurable pH range − in both deoxy and oxy HbA. They are α58, α87, α103, α122, β63, and β92.…”

Section: Resultsmentioning

confidence: 92%

“…According to Edsall’s review, it was Haldane and collaborators, who in 1914 first proposed that ″one or more acidic groups in the hemoglobin molecule became more strongly acidic when oxygen was bound to the iron″. Another interesting historical account describes the focus of Wyman and co-workers on Histidine (His) residues as the Bohr groups prior to any structural data . Mutation and chemical modification studies also suggested that the titration of histidines, particularly His β146, was involved, ,− but it was not until X-ray structures were determined by Perutz and his co-workers for unliganded (deoxy) and liganded (oxy; actually met) hemoglobin that an atomic interpretation was suggested.…”

Section: Introductionmentioning

confidence: 99%

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Hemoglobin Bohr Effects: Atomic Origin of the Histidine Residue Contributions

2013

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The Bohr effect in hemoglobin, which refers to the dependence of the oxygen affinity on the pH, plays an important role in its cooperativity and physiological function. The dominant contribution to the Bohr effect arises from the difference in the pKa values of His residues of the unliganded (deoxy) and liganded (carbonmonoxy) structures. Using recent high resolution structures, the residue pKa values corresponding to the two structures are calculated. The method is based on determining the electrostatic interactions between residues in the protein, relative to those of the residue in solution, by use of the linearized finite difference Poisson-Boltzmann equation and Monte Carlo sampling of protonation states. Given that good agreement is obtained with the available experimental values for the contribution of His residues in HbA to the Bohr effect, the calculated results are used to determine the atomic origin of the pKa shift between deoxy and carbonmonoxy HbA. The contributions to the pKa shift calculated by means of the linear response approximation show that the salt bridge involving His146 plays an important role in the alkaline Bohr effect, as suggested by Perutz but that other interactions are significant as well. A corresponding analysis is made for the contribution of His143 to the acid Bohr effect for which there is no proposed explanation. The method used is summarized and the program by which it is implemented is described in the Appendix .

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Section: Resultsmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Hemoglobin Bohr Effects: Atomic Origin of the Histidine Residue Contributions

2013

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“…In retrospect, this confirms intuition (excluding the broader TCR-CD3 complex, of course) on possibilities for a mechanism involving just the five components. Indeed, H-bonding chemistry which effects relatively simple physics is a hallmark of quite diverse protein machinery [28,29]. Also, TCR had k values that varied in either direction-indicating that conformation adjustments might moderate "flush" and "open" pitch without much increasing or decreasing of the dV, viz., R 2 ≈ 0.900 (Suppl.2).…”

Section: Discussionmentioning

confidence: 99%

“…2B). The calculus interprets a comprehensive geometry of the V-domain into a probability of scanning using only the ground-state structure, i.e., without crystallographic data on theoretical conformerssuggesting here, a classic protein function, allostery [28,29]; see also 'protein machinery' in Discussion.…”

Section: This Is Integration Of a 'Volume Element' In Spherical Coordmentioning

confidence: 99%

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

Js¹

2019

Preprint

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The mechanism which 'adapts' the T-cell antigen receptor (TCR) repertoire within a given major histocompatibility complex (MHC; HLA, in humans) genotype is essential for protection against rapidly dividing pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly "focused" towards a micromolar affinity for their respective pHLA ligands. Thus, the somatic diversity of the TCR with respect to MHC restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral equation (from fixed geometry) for any given V-domain in TCR bound to pMHC. We examined solved complexes involving HLA-DR and HLA-DQ, where all the available structures are still reasonably analysed. Certain V-beta domains displayed "rare" geometry within this panelspecifying a very low ("highly-restricted") rotational probability/volumetric density (dV). Remarkably, hydrogen (H)-bond charge-relays spanning CDR3-beta, the peptide, and polymorphic MHC distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 'scanning' on the respective MHC-II alpha-helix. Taken together, this analysis (n = 38 V-domains) supports a novel geometric theory for MHC restriction-one not constrained by a thymus "optimized" TCR-affinity.

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“…In retrospect, this might confirm intuition (excluding the broader TCR-CD3 complex, of course) on possibilities for a mechanism involving just the five components. Indeed, H-bonding chemistry which effects relatively simple physics is a hallmark of quite diverse protein machinery [24,30]. Also, TCR had k values that varied in either direction-indicating that conformation adjustments might moderate flush and open pitch without much increasing or decreasing of the dV, viz., R 2 ≈ 0.900 (Suppl.1.II).…”

Section: Dq H-bonding Mechanismsmentioning

confidence: 99%

Somatic genetics of CDR3 control TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

Murray¹

2021

Preprint

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The mechanism which adapts the T-cell antigen receptor (TCR) within a given major histocompatibility complex (MHC/HLA) genotype is essential for protection against pathogens. Historically attributed to relative affinity, genetically vast TCRs are surprisingly focused towards a micromolar affinity for their respective peptide (p) plus MHC (pMHC) ligands. Thus, the somatic diversity of the TCR with respect to MHC-restriction, and (ultimately) to pathogens, remains enigmatic. Here, we derive a triple integral solution (from fixed geometry) for any given V domain in TCR bound to pMHC. Solved complexes involving HLA-DR and HLA-DQ, where genetic linkage to the TCR is most profound, were examined in detail. Certain V domains displayed rare geometry within this panel—specifying a restricted rotational probability/volumetric density (dV). Remarkably, hydrogen (H) bond charge-relays distinguished these structures from the others; suggesting that CDR3 binding chemistry dictates CDR2 contacts on the opposite MHC-II alpha helix. Together, these data suggest that TCR recapitulate dV and specialise target pMHC recognition, i.e., a dynamics alternative to a relative TCR-affinity based mechanism.

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The BOHR effect before Perutz

Cited by 5 publications

References 18 publications

Hemoglobin Bohr Effects: Atomic Origin of the Histidine Residue Contributions

Hemoglobin Bohr Effects: Atomic Origin of the Histidine Residue Contributions

CDR3 binding chemistry controls TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

Somatic genetics of CDR3 control TCR V-domain rotational probability and germline CDR2 scanning of polymorphic MHC

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