1rvw Citations

Novel water-mediated hydrogen bonds as the structural basis for the low oxygen affinity of the blood substitute candidate rHb(alpha 96Val-->Trp).

Biochemistry 37 9258-65 (1998)
Cited: 13 times
EuropePMC logo PMID: 9649306

Abstract

One of the most promising approaches for the development of a synthetic blood substitute has been the engineering of novel mutants of human hemoglobin (Hb) A which maintain cooperativity, but possess lowered oxygen affinity. We describe here two crystal structures of one such potential blood substitute, recombinant (r) Hb(alpha 96Val-->Trp), refined to 1.9 A resolution in an alpha-aquomet, beta-deoxy T-state, and to 2.5 A resolution in a carbonmonoxy R-state. On the basis of molecular dynamics simulations, a particular conformation had been predicted for the engineered Trp residue, and the lowered oxygen affinity had been attributed to a stabilization of the deoxy T-state interface by alpha 96Trp-beta 99Asp hydrogen bonds. Difference Fourier maps of the T-state structure clearly show that alpha 96Trp is in a conformation different from that predicted by the simulation, with its indole side chain directed away from the interface and into the central cavity. In this conformation, the indole nitrogen makes novel water-mediated hydrogen bonds across the T-state interface with beta 101Glu. We propose that these water-mediated hydrogen bonds are the structural basis for the lowered oxygen affinity of rHb(alpha 96Val-->Trp), and discuss the implications of these findings for future molecular dynamics studies and the design of Hb mutants.

Reviews - 1rvw mentioned but not cited (1)



Reviews citing this publication (2)

  1. Hydrophobicity: is LogP(o/w) more than the sum of its parts? Eugene Kellogg G, Abraham DJ. Eur J Med Chem 35 651-661 (2000)
  2. Transforming growth factor-beta : biology and clinical relevance. Kim IY, Kim MM, Kim SJ. J Biochem Mol Biol 38 1-8 (2005)

Articles citing this publication (10)

  1. Chemical basis of glycine riboswitch cooperativity. Kwon M, Strobel SA. RNA 14 25-34 (2008)
  2. Computationally accessible method for estimating free energy changes resulting from site-specific mutations of biomolecules: systematic model building and structural/hydropathic analysis of deoxy and oxy hemoglobins. Burnett JC, Botti P, Abraham DJ, Kellogg GE. Proteins 42 355-377 (2001)
  3. NMR investigation of the dynamics of tryptophan side-chains in hemoglobins. Yuan Y, Simplaceanu V, Lukin JA, Ho C. J Mol Biol 321 863-878 (2002)
  4. A novel hemoglobin-based blood substitute protects against myocardial reperfusion injury. Caswell JE, Strange MB, Rimmer DM, Gibson MF, Cole P, Lefer DJ. Am J Physiol Heart Circ Physiol 288 H1796-801 (2005)
  5. Interfacial and distal-heme pocket mutations exhibit additive effects on the structure and function of hemoglobin. Maillett DH, Simplaceanu V, Shen TJ, Ho NT, Olson JS, Ho C. Biochemistry 47 10551-10563 (2008)
  6. An investigation of the distal histidyl hydrogen bonds in oxyhemoglobin: effects of temperature, pH, and inositol hexaphosphate. Yuan Y, Simplaceanu V, Ho NT, Ho C. Biochemistry 49 10606-10615 (2010)
  7. Structure-function relationship in a variant hemoglobin: a combined computational-experimental approach. Ceccarelli M, Ruggerone P, Anedda R, Fais A, Era B, Sollaino MC, Corda M, Casu M. Biophys J 91 3529-3541 (2006)
  8. Structure of Greyhound hemoglobin: origin of high oxygen affinity. Bhatt VS, Zaldívar-López S, Harris DR, Couto CG, Wang PG, Palmer AF. Acta Crystallogr D Biol Crystallogr 67 395-402 (2011)
  9. Activation of the low oxygen affinity-inducing potential of the Asn108(beta)-->Lys mutation of Hb-Presbyterian on intramolecular alpha alpha-fumaryl cross-bridging. Manjula BN, Malavalli A, Prabhakaran M, Friedman JM, Acharya AS. Protein Eng 14 359-366 (2001)
  10. Characteristic of aromatic amino acid substitution at alpha 96 of hemoglobin. Choi JW, Lee JH, Lee KH, Lee HW, Sohn JH, Yoon JH, Yeh BI, Park SK, Lee KJ, Kim HW. J Biochem Mol Biol 38 115-119 (2005)


Related citations provided by authors (2)

  1. A Novel Low Oxygen Affinity Recombinant Hemoglobin (Alpha96Val--> Trp): Switching Quaternary Structure without Changing the Ligation State. Kim HW, Shen TJ, Sun DP, Ho NT, Madrid M, Ho C J. Mol. Biol. 248 867- (1995)
  2. Production of Unmodified Human Adult Hemoglobin in Escherichia Coli. Shen TJ, Ho NT, Simplaceanu V, Zou M, Green BN, Tam MF, Ho C Proc. Natl. Acad. Sci. U.S.A. 90 8108- (1993)