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Article

Conformational Changes in Fragments D and Double-D from Human Fibrin(ogen) upon Binding the Peptide Ligand Gly-His-Arg-Pro-Amide^†^,^‡

Stephen J. Everse,^§ Glen Spraggon, Leela Veerapandian, and Russell F. Doolittle*

Center for Molecular Genetics University of California, San Diego, La Jolla, California 92093-0634

Biochemistry, 1999, 38 (10), pp 2941–2946

DOI: 10.1021/bi982626w

Publication Date (Web): February 18, 1999

†

This work was supported by Grant HL-26873 from the National Heart, Lung & Blood Institute.

‡

Atomic coordinates are available from the Brookhaven Protein Data Bank under the access codes 1FZE (DD-NL), 1FZF (DD-GH), and 1FZG (fD-GH).

Current address: Department of Biochemistry, University of Vermont, Burlington VT.

To whom correspondence should be addressed. Tel: (619) 534-4417. Fax: (619) 534-4985. E-mail: rdoolittle@ucsd.edu.

Abstract

The structure of fragment double-D from human fibrin has been solved in the presence and absence of the peptide ligands that simulate the two knobs exposed by the removal of fibrinopeptides A and B, respectively. All told, six crystal structures have been determined, three of which are reported here for the first time: namely, fragments D and double-D with the peptide GHRPam alone and double-D in the absence of any peptide ligand. Comparison of the structures has revealed a series of conformational changes that are brought about by the various knob−hole interactions. Of greatest interest is a moveable “flap” of two negatively charged amino acids (Glu^β³⁹⁷ and Asp^β³⁹⁸) whose side chains are pinned back to the coiled coil with a calcium atom bridge until GHRPam occupies the β-chain pocket. Additionally, in the absence of the peptide ligand GPRPam, GHRPam binds to the γ-chain pocket, a new calcium-binding site being formed concomitantly.

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